CN102066358A - CGRP receptor antagonists - Google Patents

CGRP receptor antagonists Download PDF

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CN102066358A
CN102066358A CN2009801220913A CN200980122091A CN102066358A CN 102066358 A CN102066358 A CN 102066358A CN 2009801220913 A CN2009801220913 A CN 2009801220913A CN 200980122091 A CN200980122091 A CN 200980122091A CN 102066358 A CN102066358 A CN 102066358A
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pyridine
difluorophenyl
tetrahydrochysene
compound
ring heptan
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CN102066358B (en
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罗光林
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Bristol Myers Squibb Co
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems

Abstract

The disclosure generally relates to the novel compounds of formula I, including their salts, which are CGRP receptor antagonists. The disclosure also relates to pharmaceutical compositions and methods for using the compounds in the treatment of CGRP related disorders including migraine and other headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases such as asthma, and chronic obstructive pulmonary disease (COPD).

Description

Piperidine derivative as the CGRP receptor antagonist
Cross reference to related application
The application requires the right of priority of the U.S. Provisional Application 61/044198 of submission on April 11st, 2008.
Technical field
The present invention relates generally to the compound of novel formula I, comprises its pharmaceutical salts, and described compound is the CGRP receptor antagonist.The present invention also relates to pharmaceutical composition and use the method for described compounds for treating CGRP associated conditions, described illness comprises migraine, nervosa vasorelaxation, nervosa inflammation, thermal damage, cyclical shock, flush, respiratory tract infection disease such as asthma and the chronic obstructive pulmonary disease (COPD) relevant with climacterium.
Background technology
Calcitonin-gene-related peptide (calcitonin gene-related peptide, CGRP) for prior to nineteen eighty-two certified naturally occurring comprise 37 amino acid whose peptides (Amara, people such as S.G., Science1982,298,240-244).Two kinds of forms of described peptide (α CGRP and β CGRP) are expressed, and the difference of these two kinds of forms is respectively an amino acid in rat, and are three amino acid in the mankind.Described peptide is distributed widely in peripheral nervous system (PNS) and the central nervous system (CNS), mainly is arranged in sensation afferent neuron and axoneuron, and shows multiple biological action, comprises vasorelaxation.
When CGRP discharges from cell, CGRP combines with specific cell surface g protein coupled receptor and mainly brings into play its biological action (Poyner by adenylate cyclase in the active cells, D.R. wait the people, Br J Pharmacol 1992,105,441-7 and Van Valen, F. wait the people, Neurosci Lett 1990,119,195-8).Based on the ability at the antagonist properties of peptide fragment CGRP (8-37) and the linear analogue activation of CGRP CGRP2 acceptor, the CGRP acceptor that proposes to have two types is that (TiPS 2000,21,432-438) for Juaneda, people such as C. for CGRP1 acceptor and CGRP2 acceptor.Yet (TiPS 2002,23,51-53) for Brain, people such as S.D. to lack molecular Evidence at the CGRP2 acceptor.The CGRP1 acceptor has three kinds of compositions: (i) seven-transmembrane Calcitonin Receptor sample acceptor (CRLR); (ii) the single-transmembrane receptor activity is regulated protein I type (RAMP1); And (iii) intracellular receptor constitutive protein (RCP) (people such as Evans B.N., JBiol Chem.2000,275,31438-43).RAMP1 is for being transported to plasma membrane with CRLR and making part and necessary (Nature 1998,393 for McLatchie, people such as L.M., 333-339) in CGRP receptors bind institute.RCP be signal transduction institute must (people such as Evans B.N., J Biol Chem.2000,275,31438-43).Known have species specificity difference in making small molecules antagonist and CGRP receptors bind, wherein typically, with regard to regard to human receptor's antagonistic action, observed affinity is higher than other species, and (TiPS 2002,23,51-53) for Brain, people such as S.D..The aminoacid sequence of RAMP1 has determined species selection, particularly, amino-acid residue tryptophane 74 be responsible for described human receptors phenotype (people such as Mallee, J BiolChem 2002,277,14294-8).
Be regarded as can be used for wherein occurring the physiological pathology illness of excessive CGRP receptor activation at the inhibitor of CGRP at receptor level.Some described illnesss comprise nervosa vasorelaxation, nervosa inflammation, migraine, cluster headache and other headache, thermal damage, cyclical shock, climacterium flush and asthma.Relevant (the Edvinsson L.CNS Drugs 2001 of the activation of CGRP acceptor with migrainous morbidity; 15 (10): 745-53; Williamson, D.J.Microsc.Res.Tech.2001,53,167-178; And Grant, A.D.Brit.J.Pharmacol.2002,135,356-362).The serum level of CGRP is the (people such as Goadsby P.J. who raises during migraine, Ann.Neurol.1990,28,183-7) and with the treatment that antimigraine drug carries out the level of CGRP is returned to and alleviate the normal level (people such as Gallai V. that headache conforms to, Cephalalgia 1995,15:384-90).The migraineur compares baseline CGRP level (people such as Ashina M., the Pain 2000,86 (1-2): 133-8) that presents rising with control patients.The CGRP of intravenous infusion produces the headache that continues (people such as Lassen L.H., Cephalalgia.2002,22 (1): 54-61) in the migraineur.The preclinical study report that dog and rat are carried out, the CGRP that blocks whole body with peptide antagonists CGRP (8-37) can not change the systemic blood kinetics when static, can not change the regional blood flow (Shen when static yet, Y-T. wait the people, J Pharmacol.Exp.Ther.2001,298,551-8).Therefore, the CGRP receptor antagonist can be used as and is used for migrainous novel therapy, and it is active vasoconstriction that described therapy can be avoided with the non-selective 5-HT1B/1D agonist cardiovascular tendency that promptly " triptan (triptan) " (for example sumatriptan (sumatriptan)) is relevant.
The CGRP antagonist has demonstrated usefulness in the human clinical trial.Referring to Davis CD, Xu C.Curr Top Med Chem.20088 (16): 1468-79; Benemei S, Nicoletti P, Capone JG, Geppetti P.Curr Opin Pharmacol.20099 (1): 9-14.Epub 2009 Jan 20; Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, Leibensperger H, Froman S, Assaid C, Lines C, Koppen H, Winner PK.Lancet.2008372:2115.Epub 2008Nov 25; Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, Lines CR, Rapoport AM; With Neurology 200870:1304.Epub 2007Oct 3.
The invention provides technological merit, for example described compound is novel and suppresses CGRP.In addition, described compound provides the advantage at pharmaceutical use, for example the following character of one or more of described compound: mechanism of action, binding mechanism, inhibition usefulness, target selectivity, solvability, security or bioavailability.
The CGRP receptor antagonist has been disclosed among PCT open text WO 2004/092166, WO2004/092168 and the WO 2007/120590.
Description of drawings
Fig. 1 .[ 125I]-CGRP is saturated/and Scatchard analyzes.[1 25IThere is not CGRP antagonist embodiment 20 (closed square) in the saturated use of]-CGRP SK-N-MC film and is existing the situation of CGRP antagonist embodiment 20 (all other signs) to get off to carry out.
Fig. 2. functional antagonism/Schild analyzes.CGRP dose response (cAMP through stimulating produces) gets off to carry out in the situation that does not have CGRP antagonist embodiment 20 (hollow square) and exist concentration to increase the CGRP antagonist embodiment 20 (all identify) of (be from left to right 0.3 to 24nM) in the SK-N-MC cell.
Fig. 3. in rat to directly determining that the facial blood flow of representing the entocranial artery diastole carries out.The h α CGRP of intravenous administration is inducing comparable increase percentage ratio (100-120% of baseline) aspect rat arteria meningea media diameter and the facial blood flow of rat (being respectively left side striped post and right side striped post).With regard to these two were measured, the pretreatment of carrying out with peptide antagonists CGRP (8-37) suppressed (solid post) to the h α CGRP generation 50% of intravenous administration subsequently.In every animal (n=5 rat), measure entocranial artery diameter and facial blood flow simultaneously.Data are mean value ± sem, wherein compare with corresponding h α CGRP separately, and * is p＜0.05, and * * is p＜0.01.
Fig. 4. aspect the facial blood flow of non-human primate's laser-Doppler to the dose response of h α CGRP.The h α CGRP of intravenous administration is inducing the dose-dependently increase aspect the facial blood flow of non-human primate's (for example common marmoset) laser-Doppler.Animal (n=6) is to accept to increase the h α CGRP of dosage in 30 minutes at interval.Data are the percent change ± sem of peak with respect to baseline, and wherein every animal is as the contrast of himself.
Summary of the invention
The present invention contains a series of CGRP agonist compounds (comprising its pharmaceutical salts), composition, prepare the method for these compounds and use the method for these compounds in therapeutic is disposed.
One aspect of the invention is the compound or pharmaceutically acceptable salt thereof of formula I:
Figure BPA00001276869200041
Wherein
R 1Be hydrogen, cyano group, halogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, alkyl SO 2, amino, alkylamino, dialkyl amido, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, N-alkylpiperazine base or morpholinyl;
R 2Be selected from a following substituent piperidyl for being substituted with:
Figure BPA00001276869200042
Or R 2For
Figure BPA00001276869200043
R 3Be hydrogen, halogen, cyano group, alkyl, haloalkyl, alkoxyl group or halogenated alkoxy;
R 4Be hydrogen, halogen, cyano group, alkyl, haloalkyl, alkoxyl group or halogenated alkoxy;
Ar 1Be selected from following 0-3 substituent phenyl for being substituted with: cyano group, halogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy and alkyl SO 2
X is O, CH 2Or NH; And
Y is chemical bond, O, CH 2Or NH.
Another aspect of the present invention is the compound or pharmaceutically acceptable salt thereof of formula I, wherein
R 1Be hydrogen, cyano group, amino, alkylamino or dialkyl amido;
R 2Be selected from a following substituent piperidyl for being substituted with:
Or R 2For
Figure BPA00001276869200052
R 3Be hydrogen or halogen;
R 4Be hydrogen or halogen;
Ar 1For being substituted with the phenyl of 0-2 halogenic substituent;
X is O, CH 2Or NH;
And Y is O.
Another aspect of the present invention is the compound or pharmaceutically acceptable salt thereof of formula I, wherein R 1Be hydrogen, cyano group, amino, dimethylamino or tertiary butyl amino; R 2Be selected from a following substituent piperidyl for being substituted with:
Figure BPA00001276869200053
Or R 2For
Figure BPA00001276869200054
Ar 1Be phenyl or difluorophenyl; X is O, CH 2Or NH; And Y is O.
Another aspect of the present invention is the compound of formula I, wherein R 1Be hydrogen or cyano group.
Another aspect of the present invention is the compound of formula I, wherein R 2Replace for the N-piperidyl and at 4.
Another aspect of the present invention is the compound of formula I, wherein R 2Be substituted with for the N-piperidyl and at 4 and be selected from following substituting group:
Another aspect of the present invention is the compound of formula I, wherein Ar 1For being substituted with the phenyl of 2 halogenic substituents.
Another aspect of the present invention is the compound of formula I, wherein Ar 1Be 2, the 3-difluorophenyl.
Another aspect of the present invention is the compound of formula I, and wherein X is O.
Another aspect of the present invention is the compound with following stereochemical formula I:
Figure BPA00001276869200062
Another aspect of the present invention is the compound or pharmaceutically acceptable salt thereof of formula II:
Figure BPA00001276869200063
Wherein
R 2For piperidyl and be substituted with and be selected from a following substituting group:
Figure BPA00001276869200064
Or R 2For
Figure BPA00001276869200065
R 3Be hydrogen or alkyl;
R 4Be hydrogen, halogen, cyano group, alkyl, haloalkyl, alkoxyl group or halogenated alkoxy;
Ar 1Be selected from following 0-3 substituent phenyl for being substituted with: cyano group, halogen, alkyl, haloalkyl, alkoxyl group and halogenated alkoxy;
X is O, CH 2Or NR 3
Y is chemical bond, methylene radical, O or NR 3
Variable (comprises R 1, R 2, R 3, R 4, Ar 1, X and Y) the scope of any example can be independent of the scope of substituent any other example of variable and use.Therefore, the present invention includes the combination of different aspect.
Except as otherwise noted, these terms have following meaning." alkyl " means by 1 to 6 carbon and is preferably the straight or branched alkyl that 1 to 3 carbon constitutes." thiazolinyl " means the straight or branched alkyl that is constituted and had at least one two key by 2 to 6 carbon." cycloalkyl " means the monocycle ring system that is made of 3 to 7 carbon." hydroxyalkyl ", " alkoxyl group " and other term with moieties of replacement comprise with regard to moieties by 1 to 6 straight chain that carbon atom constitutes and branched chain isomer." haloalkyl " reaches " halogenated alkoxy " and comprises the alkyl that replaces from single halogen all halogenation isomer to the plain alkyl that replaces of perhalogeno." aryl " comprises carbocyclic aromatic ring system and heterocyclic aromatic ring system." amino " comprises primary amino part, secondary amino group part and the amino part of uncle." carbonyl " means CO." oxygen base " means-O-." aminocarboxyl " mean-N (R) C (=O)-." oxygen base carbonyl " mean-OC (=O)-." methylene radical carbonyl " means-CH 2C (=O)-." amino (cyano group) iminomethyl " mean-NHC (=NCN)-.The term that comprises bracket and multiple bracket is intended to illustrate the bonding relation to those skilled in the art.For example, term such as ((R) alkyl) means and further is substituted the alkyl substituent that basic R replaces.
The present invention includes all pharmaceutical salts forms of described compound.Pharmaceutical salts is the physiologically active of the wherein described compound of not remarkably influenced of counter ion or toxicity and the function salt as the pharmacology equivalent.These salt can have machine technology to use the commercial reagent to prepare according to common.Some anion salt forms comprise acetate, acistrate, benzene sulfonate, bromide, muriate, citrate, fumarate, glucuronate, hydrobromate, hydrochloride, hydriodate, iodide, lactic acid salt, maleate, mesylate, nitrate, pamoate, phosphoric acid salt, succinate, vitriol, tartrate, tosylate and xinafoate.Some cationic salts forms comprise ammonium salt, aluminium salt, benzyl star salt, bismuth salt, calcium salt, choline salt, diethyl amine salt, diethanolamine salt, lithium salts, magnesium salts, meglumine salt, 4-phenyl cyclohexylamine salt, piperazine salt, sylvite, sodium salt, tromethamine salt and zinc salt.
Some compounds of the present invention can exist by stereoisomeric forms in any ratio, and its a kind of example is as follows.The present invention includes all stereoisomeric forms in any ratio and the tautomeric form of described compound.
Figure BPA00001276869200081
Synthetic method
The compounds of this invention can prepare by methods known in the art (comprise those methods that describe below and comprise the variant that the art technology scope is interior).Some reagent and intermediate are known in the art.Other reagent and intermediate can use the material that is easy to obtain to prepare by methods known in the art.Following method for purpose of explanation but not be intended to limit the scope of the invention.It will be understood by those skilled in the art that the method that provides among the following embodiment is provided for have the multiple method that can be used for synthetic these compounds and these compounds synthetic.Unaccounted compound variant and prepare the operating in the art technology scope of these variants.The variable of describing general structural formula and feature in synthetic schemes is different from the variable in claims or the specification sheets rest part and should obscure with it.These variablees only are used for explanation and how prepare some compounds of the present invention.
The abbreviation of using in scheme meets the usual meaning of this area usually.The chemical abbreviations of using in specification sheets and embodiment is as giving a definition: " NaHMDS " represents two (trimethyl silyl) sodium amide; " DMF " represents N, dinethylformamide; " MeOH " represents methyl alcohol; " NBS " expression N-bromine succinimide; " Ar " represents aryl; " TFA " represents trifluoroacetic acid; " LAH " represents lithium aluminium hydride; " BOC " expression tertbutyloxycarbonyl, " DMSO " represent dimethyl sulfoxide (DMSO); " h " expression hour; " rt " expression room temperature or retention time (depending on the circumstances); " min " expression minute; " EtOAc " represents ethyl acetate; " THF " represents tetrahydrofuran (THF); " EDTA " represents ethylenediamine tetraacetic acid (EDTA); " Et 2O " the expression ether; " DMAP " represents 4-dimethylaminopyridine; " DCE " expression 1, the 2-ethylene dichloride; " ACN " represents acetonitrile; " DME " expression 1, the 2-glycol dimethyl ether; " HOBt " expression I-hydroxybenzotriazole hydrate; " DIEA " represents diisopropyl ethyl amine, and " Nf " represents CF 3(CF 2) 3SO 2-; And " TMOF " represents trimethyl orthoformate.
Following proposal has illustrated the method for the compound that can be used for preparation formula I.The synthetic method that scheme I describes starts from compound III, and it is known by being purchased the compound of raw material by the single stage method preparation for document.The reaction of III and metal arylide reagent (such as ArLi or ArMgX) can form IV, and IV can (ring-closure metathesis RCM) forms V down at the cyclization metathesis reaction.Tertiary alcohol V can carry out dehydroxylation with formation alkene VI, and V can obtain glycol VII under standard dihydroxy condition.Single protection of glycol can obtain VIII, and VIII is oxidable to obtain the hydroxyketone IX through protection.The popular response of modifying alcohol, ketone or alpha-carbon can obtain the compound of other formula I.Selectively, IX can modify to obtain multiple condensed heterocycle and the cycloheptane derivative as X.Deprotection can obtain corresponding pure XI, and pure XI can activate and with the reaction of different amine to obtain the wherein compound of the formula II of X=O.The also oxidable one-tenth ketone of XI XIII then carries out carbochain and prolongs (Wittig), reduction and hydrolysis obtaining sour XIV, and sour XIV forms reaction by acid amides and can obtain wherein X=CH 2The compound of formula II.Selectively, pure XI can be converted into amine, then carries out urea and forms reaction to obtain the wherein compound of the formula II of X=NH.Scheme 2 provides the optional method of the compound of preparation formula I.This method is used the Grubbs ring-closure reaction, then is converted into ketone, and described ketone can be introduced aryl moiety then.Further processing is to obtain alcohol, and described alcohol can transform by methods known in the art then.
Scheme 1
Figure BPA00001276869200091
Scheme 2 has been described the certain methods of using the Grubbs ring-closure reaction to obtain condensing the suberane ring of pyridine ring structure.Further processing is to obtain the compound of formula I.
Scheme 2
Scheme 3 has been described the optional method that uses the Grubbs ring-closure reaction to obtain condensing the suberane ring of pyridine ring structure.Further processing is to obtain the compound of formula I.
Scheme 3
Figure BPA00001276869200111
Scheme 4 has been described the optional method that the suberane articulating that obtains condensing the pyridine ring structure selective reduction diketone intermediate.Further processing is to obtain the compound of formula I.
Scheme 4
Figure BPA00001276869200121
Scheme 5 has been described and has been obtained having the method that the carbon that links to each other with condensed pyrido suberane parent nucleus is connected the compound of basic formula I.
Scheme 5
Figure BPA00001276869200131
Scheme 6 has been described the extra substituent certain methods of generation on condensed pyrido suberane parent nucleus.Further processing is to obtain the compound of formula I.
Scheme 6
Figure BPA00001276869200141
Scheme 7 has been described the certain methods of the extra aryl substituent of on condensed pyrido suberane parent nucleus generation.Further processing is to obtain the compound of formula I.
Scheme 7
Figure BPA00001276869200151
Scheme 8 has been described on condensed pyrido suberane parent nucleus and have been produced extra nitrogen and connect substituent certain methods.Further processing is to obtain the compound of formula I.
Scheme 8
Figure BPA00001276869200161
Scheme 9 has been described the certain methods of the N-oxide compound analogue that obtains pyrido suberane parent nucleus.Further processing is to obtain the compound of formula I.
Scheme 9
Biological method
External pharmacology
Tissue culture
Constitute by the MEM that contains Earl ' s salt and L-glutaminate (Invitrogen) and be supplemented with make in the substratum of 10% foetal calf serum (Invitrogen) the SK-N-MC cell with individual layer at 37 ℃ and 5%CO 2Middle growth.
Membrane prepare
Thick film is by the SK-N-MC cell preparation of expressing the CGRP acceptor.Cell phosphate buffered saline (PBS) (155mM NaCl, 3.3mM Na 2HPO 4, 1.1mM KH 2PO 4, pH 7.4) twice of drip washing and in the low vadose solution born of the same parents damping fluid that constitutes by 10mM Tris (pH 7.4) and 5mM EDTA, cultivated 5-10 minute at 4 ℃.Cell is transferred to polypropylene tube (in 16 * 100mm) and use many rotors (polytron) to come homogenize from culture plate.Homogenize thing centrifugal 30 minutes with 32,000 * g.The precipitation agglomerate is suspended in the cold low vadose solution born of the same parents damping fluid that contains 0.1% mammalian protease inhibitor mixed agent (Sigma) again and measures protein concn.SK-N-MC homogenize thing separatory such as is divided into and is stored in-80 ℃.
Radioligand is in conjunction with mensuration
The compounds of this invention uses 100%DMSO to come solubilising and carry out serial dilution.The separatory that waits that comes from the compound serial dilution is being measured damping fluid (50mM Tris-Cl pH 7.5,5mM MgCl again 2, 0.005%Triton X-100) in 25 times of dilutions and shift (volume is 50 microlitres) to 96 hole assay plate.Will [ 125I]-CGRP (GE Healthcare or Perkin-Elmer) is diluted in to measure in the damping fluid to concentration and is 72pM and is added in each hole with the volume of 50 microlitres.The SK-N-MC film is thawed, be diluted in the mensuration damping fluid that contains fresh 0.1% mammalian protease inhibitor mixed agent (Sigma) and homogenize once more.Volume with 100 microlitres adds SK-N-MC homogenize thing (7 micrograms/hole).Then with assay plate incubated at room temperature 2 hours.Add excessive cold lavation buffer solution (50mM Tris-Cl pH 7.5,0.1%BSA), stop thus measuring, then use pre-soaked glass fibre filter (Whatman GF/B) in 0.5%PEI to filter immediately.Non-specific binding defines with 1 μ M β-CGRP (Bachem).The protein bound radioactivity uses gamma counter or scintillometer to determine.Resulting data use four parameters competitions to analyze in conjunction with equation (XLfit v2.0) and with IC 50Be defined as displacement 50% radioligand in conjunction with needed The compounds of this invention concentration.[ 125I]-the final mensuration concentration of CGRP is 18pM.At [ 125I]-the average Kd of CGRP is 25.4pM.All compounds of the present invention are independently estimated in the experiment at least twice.Sum up referring to the data in the table 1.
The human CGRP combination of table 1.
Embodiment Human CGRP acceptor IC 50(nM)
1 2.86
2 0.23
3 1.25
4 0.44
5 4.04
6 0.89
7 ＞100
8 1.60
9 ＞1000
Embodiment Human CGRP acceptor IC 50(nM)
10 8.89
11 4.14
12 7.41
13 1.55
14 0.25
15 0.98
16 6.96
17 0.80
18 0.78
19 0.76
20 0.12
21 0.12
Saturated/Scatchard analyzes
Interaction essence between human CGRP peptide and the embodiment 20 uses saturated combination experiment to study in great detail.The concentration increase [ 125I]-there is not embodiment 20 (collating condition) in being combined in of CGRP and SK-N-MC cytolemma and has 300pM and the measurement of getting off of the situation of 600pM embodiment 20.Saturated data use single site to analyze to assess apparent equilibrium dissociation constant (K in conjunction with equation d) and binding site maximum number (B Max) (Prizm v4.0, Graphpad).The adding of measuring and having compared embodiment 20 to [ 125I]-CGRP bonded incorporating parametric (K dAnd B Max) influence.Embodiment 20 dose-dependently ground increased [ 125I]-CGRP bonded K d, and do not change [with having significance 125I]-CGRP bonded binding site maximum number (B Max).This show embodiment 20 to [ 125I]-CGRP bonded inhibition mechanism is emulative.Embodiment 20 independently estimates that (data set is for example referring to " Fig. 1 .[in the experiment at 3 times 125I]-CGRP is saturated/and Scatchard analyzes ").
Functional antagonism/Schild analyzes
The agonist of CGRP receptor complex stimulated cause cAMP (cyclic AMP) (the single adenosine phosphate of 3 ' 5 '-ring-type) to activate producing (Juaneda C et al., TiPS, 2000 via the Gs dependency of adenylate cyclase; 21:432-438).Therefore, the CGRP receptor antagonist suppresses to form (Doods H et al., Br J Pharmacol, 2000 by CGRP inductive cAMP in the SK-N-MC cell of natural expression CGRP receptor complex; 129 (3): 420-423).The ability that embodiment 20 blocking-up are formed by CGRP inductive cAMP is used the cAMP HTRF test kit that is purchased, and (catalog number 62AM2PEC CisBioInternational) estimates.Use the Schild analytical model, it can be used for studying antagonism mechanism.In this pattern, the dose response that the cAMP that is stimulated by CGRP produces only exists CGRP and following the obtaining of situation that has the embodiment 20 of various concentration.In brief, embodiment 20 was cultivated 15 minutes in advance with the SK-N-MC cell.Add the CGRP of various concentration and with cell incubated at room temperature 30 minutes.Cell is determined according to manufacturer specification by HTRF with molten born of the same parents' agent dissolves and cAMP concentration.The typical curve that the cAMP that uses known quantity is obtained carries out parallel evaluation so that HTRF ratio is scaled nM cAMP.Resulting then curve uses Gaddum/Schild equation [independent use and with overall fit coupling], and (Prizm v4.0 Graphpad) estimates.Embodiment 20 causes CGRP EC 50Move to right but do not change peak response.In order to obtain overall fit, share following parameter (top value (top), floors (bottom), logEC 50, Hill slope and pA2) and all curves of match simultaneously.For twice independently experiment, the resulting Schild slope value of the overall fit of using non-limiting Schild slope to carry out is 1.17 and 0.8, consistent (methodology is referring to Moltulsky et al. with about 1 the Schild slope of being contemplated to of simple competitive antagonist for this, 2003, Graphpad Software Inc.).The average K of two group data sets of embodiment 20 b(the Schild slope of use is 1) be 247 ± 40pM (at the Schild slope be under 1 the situation just the overall fit data set marked and drawed of embodiment 20 for example referring to " Fig. 2. functional antagonism/Schild analyzes ").
Measure the non-terminal method of usefulness in the body of small molecules CGRP receptor antagonist in Mammals
General introduction
Proposed to be used for migrainous treatment (Edvinsson et al CNS Drugs200115:745 to blocking-up by calcitonin-gene-related peptide (CGRP) inductive cascade event (comprising the nervosa vasorelaxation of entocranial artery); Benemei et al Curr Opin Pharmacol 20099:9), yet novel small molecules CGRP receptor antagonist has demonstrated species specificity difference, and demonstrate weak relatively activity (Mallee et al.J Biol Chem 2002277:14294) in rodent, this needs new model to estimate usefulness in the body.Non-human primate (for example marmoset monkey) is the known pharmacological unique animal of proper manners CGRP acceptor that has, this following confirmation: have specific amino acid residue (Trp74) in their RAMP1 sequence, it is the feature (Mallee et al.J Biol Chem 2002277:14294) of described human receptor's phenotype.Because present Nerve in Migraine Model is mainly used rat (Escott et al.Brain Res1995669:93 and Williamson et al.Cephalalgia 199717:525) or the terminal operation of the invasive that carries out (terminal procedure) (Doods et al.Br J Pharmacol 2000129:420) in primate, so develop the novel Noninvasive survival model of in the non-human primate, estimating usefulness in the CGRP receptor antagonist body.Although known trifacial activation had both increased encephalic blood flow (Goadsby ﹠amp; Edvinsson, 1993) increase facial blood flow (Doods et al., 2000) again, but in same animal, the direct relation between facial blood flow and the entocranial artery diastole is confirmed not to be known.Therefore, before beginning is studied in the non-human primate, in rat, directly the facial blood flow of representing encephalic auterial diastole in the terminal research is carried out laser Doppler measuring, this in same animal, not only measured the entocranial artery diameter but also measured facial blood flow change (referring to " and Fig. 3. in rat to the facial blood flow of represent the entocranial artery diastole carry out directly definite ").In these two measurements, comparable increase is induced by intravenous administration CGRP and is blocked by peptide antagonists h α CGRP (8-37).Then determined to induce by intravenous administration CGRP the method for facial blood flow change, it is to recover model with regard to the rat of the use h α CGRP (8-37) of usefulness isoflurane anesthesia.In the non-human primate, implement this rodent survival method then, and finish dosage-response investigations that intravenous administration CGRP activity is characterized (referring to " and Fig. 4. aspect the facial blood flow of non-human primate's laser-Doppler to the dose response of h α CGRP ").Peptide and small molecules CGRP receptor antagonist are used for determining non-human primate's model.The facial blood flow of primate that the pretreatment dose-dependently ground that carries out with small molecules antagonist or h α CGRP (8-37) has suppressed the CGRP by intravenous administration and stimulated increases (referring to " table 2. is in the inhibition to being increased by the CGRP inductive aspect the facial blood flow of non-human primate's (for example common marmoset) laser-Doppler ").The back disposal of carrying out with antagonist has also reversed by the facial blood flow increase of CGRP inductive (not shown).This survival model provides novel Noninvasive recovery operation, it is used for estimating the CGRP receptor antagonist in non-human primate or the prevention and the interruption effect that have human RAMP1 (Trp74) and have the pharmacological transgenic animal of similar CGRP acceptor, its just with regard to the activity of entocranial artery diameter as representative sign.
Animal
Bull and female common marmoset (Callithrix jacchus) are that 350-550g person is as study subject available from Harlan and body weight.
Anesthesia and operation are prepared
Animal is anaesthetized and (keeps with the 4-5% rapid induction and with 1-2.5% by sucking isoflurane in induction room; Solomon et al., 1999).Anaesthetize following keeping: continue to send air via face shield or by intubate and ventilation (with the blood gas monitoring): oxygen (50: 50) and isoflurane.Body temperature maintains 38 ± 0.5 ℃ by placing on the automatization temperature control table face with transrectal probe.By using depilatory cream and/or carrying out shaving and remove a small pieces fur (about 1.5cm by a side surface part or both sides face 2).The clamping operative region is also handled with povidone iodine.Place any available vein (for example saphena) with administration test compounds and CGRP receptor stimulant intravenous line, and if desired, then extract blood sample (maximum 2.5ml, 10%) to carry out blood gas monitoring and content analysis.When research finished, intravenous administration 5% glucose solution was to keep glucose level.The following monitoring of depth of anesthesia: use Noninvasive arm sleeve pipe method and pulse oximeter to measure blood pressure and heart rate respectively.But intravenous administration guanethidine 5-10mg/kg (being supplemented with the 5mg/kg of intravenous administration as required) be stabilized in repetitious stimulation-induce blood flow change in observed facial blood stream peaks flux (Escott et al., 1999).The following monitoring of capillary blood vessel blood flow: will self have the laser-Doppler flow probe and the skin of face attachment of viscosity.
Compound administration
Test compounds can following administration: intravenous administration (0.01-5ml/kg), intramuscular administration (0.01-0.5ml/kg), subcutaneous administration (0.01-5ml/kg) or oral administration (0.1-10ml/kg) (Diehl et al., 2001).The CGRP receptor stimulant can following administration: intravenous administration (0.01-5ml/kg), intradermal administration (10-100 μ l/ site) or subcutaneous administration (10-100 μ l/ site).
Laser Doppler flowmeter
The contrast of facial blood flow increases induces by administration vasodilator such as CGRP (intravenous administration 0.05-100 μ g/kg or intradermal administration 2-20pmol/ site).Test compounds or vehicle before the repeat administration vasodilator (pretreatment) or afterwards (then dispose) come administration, this provides the ability of estimating prophylactic effect or therapeutic action.Continue to monitor blood pressure guaranteeing enough depth of anesthesia, and adjust narcotic to keep the maintenance level with pretreatment value coupling.During gathering the laser Doppler flowmeter data, isoflurane can be reduced to 0.25-0.75%, this is because find in the marmoset monkey electrophysiologic studies formerly that the record result is responsive (Solomon, 1999) to isoflurane concentration.In order to reduce the number of used animal, the effect that test compounds changes the vasodilator inductive blood flow by intravenous administration can be repeated in an experiment periods many 6 times.
Recover
Animal is returned in the transhipment cage, and described transhipment cage is placed on the temperature control table face so that animal keeps warm up to reviving fully and the energy activity.Animal can be tested afterwards once more at rest 7-14 days, and can come repeated test according to the animal health situation at interval by 7-14 days.
Referring to Diehl KH, Hull R, Morton D, Pfister R, Rabemampianina Y, Smith D, Vidal JM, van de Vorstenbosch C.A good practice guide to the administration ofsubstances and removal of blood, including routes and volumes.J Appl Toxicol.2001 Jan-Feb; 21 (1): 15-23; Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W.Pharmacological profile of BIBN4096BS, thefirst selective small molecule CGRP-receptor antagonist.Br J Pharmacol.2000Feb; 129 (3): 420-3; Edvinsson L.Calcitonin gene-related peptide (CGRP) and thepathophysiology of headache:therapeutic implications.CNS Drugs 2001; 5 (10): 745-53; Escott KJ, Beattie DT, Connor HE, Brain SD.Trigeminal ganglionstimulation increases facial skin blood flow in the rat:a major role for calcitoningene-related peptide.Brain Res.1995 Jan 9; 669 (1): 93-9; Goadsby PJ, Edvinsson L.The trigeminovascular system and migraine:studies characterizingcerebrovascular and neuropeptide changes seen in humans and cats.Ann Neurol.1993 Jan; 33 (1): 48-56; Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olsen J.CGRP may play a causative role in migraine.Cephalalgia, 2002,22,54-61; Mallee JJ, Salvatore CA, LeBourdelles B, Oliver KR, Longmore J, Koblan KS, Kane SA.RAMP1 determines the species selectivity ofnon-peptide CGRP receptor antagonists.J Biol Chem.2002 Feb 14[epub aheadof print]; Solomon SG, White AJ, Martin PR.Temporal contrast sensitivity in thelateral geniculate nucleus of a New World monkey, the marmoset Callithrixjacchus, J Physiol.1999 Jun 15; 517 (Pt 3): 907-17.
Table 2. is aspect the facial blood flow of non-human primate's (for example common marmoset) laser-Doppler
To the inhibition that increases by the CGRP inductive
Figure BPA00001276869200231
Pharmaceutical composition and methods of treatment
The compound of formula I suppresses the CGRP acceptor.Therefore, they can be used for treating illness or obstacle relevant with unusual CGRP level or wherein can have the treatment benefit to the adjusting of CGRP level.
Therefore, another aspect of the present invention is a pharmaceutical composition, and it comprises compound and pharmaceutical excipient, carrier or the thinner of formula I.
Compound comes administration with the form of pharmaceutical composition usually, described pharmaceutical composition by the treatment significant quantity formula I compound or pharmaceutically acceptable salt thereof and pharmaceutical carrier constitutes and can contain conventional excipient.The treatment significant quantity provides significant patient's benefit needed amount for what those skilled in the art determined.Pharmaceutical carrier is to have the conventional known carrier that can accept security.Composition is contained all common solid and liquid forms, comprises capsule, tablet, lozenge and powder agent and liquid suspension, syrup, tincture and solution.Solids composition can be configured as time release formulation or extended release preparation.Composition uses ordinary preparation technology and conventional excipient (such as tackiness agent and wetting agent) and vehicle (such as water and alcohol) to prepare.
About 1 dose unit to about 1000 milligrams of activeconstituentss is provided when usually solids composition being mixed with each administration.Some examples of solid dosage unit are 0.1 milligram, 1 milligram, 10 milligrams, 100 milligrams, 500 milligrams and 1000 milligrams.The unitary dose scope of liquid composition is generally the 1-100 mg/ml.Some examples of liquid dosage unit are 0.1 mg/ml, 1 mg/ml, 10 mg/ml, 25 mg/ml, 50 mg/ml and 100 mg/ml.
All conventional mode of administration are contained in the present invention, comprise method in the oral methods, parenteral method, nose, hypogloeeis method and through the skin method.Typically, per daily dose will be 0.01-100 mg/kg body weight every day.Usually, oral methods needs more compound, and the parenteral method needs less compound.Yet concrete dosage regimen should use rational medicine to judge to determine by the doctor.
Be regarded as can be used for wherein having occurred the physiological pathology illness of excessive CGRP receptor activation at the inhibitor of CGRP at receptor level.Some described illnesss comprise nervosa vasorelaxation (neurogenicvasodilation), nervosa inflammation (neurogenic inflammation), migraine (migraine), cluster headache (cluster headache) and other headache, thermal damage (thermal injury), cyclical shock (circulatory shock), climacterium flush (menopausal flushing) and asthma (asthma).The activation of CGRP acceptor relevant (Edvinsson L.CNS Drugs 2001,15 (10), 745-53 with migrainous morbidity; Williamson, D.J.Microsc.Res.Tech.2001,53,167-178; And Grant, A.D.Brit.J.Pharmacol.2002,135,356-362).The serum level of CGRP is the (people such as Goadsby P.J. who raises during migraine, Ann.Neurol.1990,28,183-7) and with the treatment that antimigraine drug carries out the level of CGRP is returned to and alleviate the normal level (people such as Gallai V. that headache conforms to, Cephalalgia 1995,15:384-90).The migraineur compare with control patients the baseline CGRP level that presents rising (people such as Ashina M., Pain 2000,86 (1-2), 133-8).The CGRP of intravenous infusion in the migraineur, produce the headache that continues (people such as Lassen L.H., Cephalalgia.2002,22 (1), 54-61).The preclinical study report that dog and rat are carried out, the CGRP that blocks whole body with peptide antagonists CGRP (8-37) can not change the systemic blood kinetics when static, can not change the regional blood flow (Shen when static yet, Y-T. wait the people, J Pharmacol.Exp.Ther.2001,298,551-8).Therefore, the CGRP receptor antagonist can be used as and is used for migrainous novel therapy, and it is active vasoconstriction that described therapy can be avoided with the non-selective 5-HT1B/1D agonist cardiovascular tendency that promptly " triptan " (for example sumatriptan) is relevant.
Another aspect of the present invention is for suppressing the method for CGRP acceptor, and it comprises makes the CGRP acceptor contact with the compound or pharmaceutically acceptable salt thereof of formula I.
Another aspect of the present invention is the method for treatment with the illness of unusual CGRP level, and it comprises the compound to the formula I of patient's drug treatment significant quantity.
Another aspect of the present invention is that the compound of formula I is used for the treatment of purposes in the medicine of the illness relevant with unusual CGRP level in preparation.
Another aspect of the present invention is the method for treatment migraine or headache.
Another aspect of the present invention relates to the method for the treatment of following disease: inflammation (especially nervosa inflammation), pain, thermal damage, cyclical shock, diabetes, Raynaud syndrome (Reynaud ' s syndrome), peripheral arterial deficiency (peripheral arterial insufficiency), under the arachnoid membrane/cranium hemorrhage (subarachnoid/cranial hemorrhage), tumor growth, the flush relevant and can comprise other illness that the pharmaceutical composition of compound of the formula (I) of the application definition comes antagonism CGRP acceptor to play a role by administration to its treatment of carrying out with climacterium.
Another aspect of the present invention relates to the following method that is selected from: (a) carry out immunomodulatory, (b) and take protective measure, (c) to stimulate to heart allergy damage (cardiac anaphylactic injury) or prevention il-1 b (IL-1b) regulates in the notochord neurone (spinal neuron) NK1 receptor expression and (e) treatment air flue inflammatory diseases and chronic obstructive pulmonary disease (comprising asthma) to stimulation, (d) of bone resorption in intestinal mucosa.Referring to: (a) Calcitonin Receptor-Like Receptor Is Expressed onGastrointestinal Immune Cells.Hagner, Stefanie; Knauer, Jens; Haberberger, Rainer; Goeke, Burkhard; Voigt, Karlheinz; McGregor, Gerard Patrick.Instituteof Physiology, Philipps University, Marburg, Germany.Digestion (2002), 66 (4), 197-203; (b) Protective effects of calcitonin gene-related peptide-mediatedevodiamine on guinea-pig cardiac anaphylaxis.Rang, Wei-Qing; Du, Yan-Hua; Hu, Chang-Ping; Ye, Feng; Tan, Gui-Shan; Deng, Han-Wu; Li, Yuan-Jian.Schoolof Pharmaceutical Sciences, Department of Pharmacology, Central SouthUniversity, Xiang-Ya Road 88, Changsha, Hunan, Naunyn-Schmiedeberg ' sArchives of Pharmacology (2003), 367 (3), 306-311; (c) The experimental studyon the effect calcitonin gene-related peptide on bone resorption mediated byinterleukin-1.Lian, Kai; Du, Jingyuan; Rao, Zhenyu; Luo, Huaican.Departmentof Orthopedics, Xiehe Hospital, Tongji Medical College, Huazhong Universityof Science and Technology, Wuhan, Peop.Rep.China.Journal of Tongji MedicalUniversity (2001), 21 (4), 304-307; (d) Calcitonin gene-related Peptide regulatesexpression of neurokinin 1 receptors by rat spinal neurons.Seybold VS, McCarson KE, Mermelstein PG, Groth RD, Abrahams LG.J.Neurosci.200323 (5): 1816-1824.epartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas66160; (e) Attenuation of antigen-induced airway hyperresponsiveness inCGRP-deficient mice.Aoki-Nagase, Tomoko; Nagase, Takahide; Oh-Hashi, Yoshio; Shindo, Takayuki; Kurihara, Yukiko; Yamaguchi, Yasuhiro; Yamamoto, Hiroshi; Tomita, Tetsuji; Ohga, Eijiro; Nagai, Ryozo; Kurihara, Hiroki; Ouchi, Yasuyoshi.Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.American Journal of Physiology (2002), 283 (5, Pt.1), L963-L970; (f) Calcitonin gene-related peptide as inflammatorymediator.Springer, Jochen; Geppetti, Pierangelo; Fischer, Axel; Groneberg, David A.Charite Campus-Virchow, Department of Pediatric Pneumology andImmunology, Division of Allergy Research, Humboldt-University Berlin, Berlin, Germany.Pulmonary Pharmacology ﹠amp; Therapeutics (2003), 16 (3), 121-130; (g) Pharmacological targets for the inhibition of neurogenic inflammation.Helyes, Zsuzsanna; Pinter, Erika; Nemeth, Jozsef; Szolcsanyi, Janos.Department ofPharmacology and Pharmacotherapy, Faculty of Medicine, University of Pecs, Pecs, Hung.Current Medicinal Chemistry:Anti-Inflammatory ﹠amp; Anti-AllergyAgents (2003), 2 (2), 191-218.
Another aspect of the present invention relates to the compound of combined type I and treats migrainous method with one or more medicines that are selected from cox 2 inhibitor, NSAIDS, acetylsalicylic acid, paracetamol, triptan, Ergotamine and caffeine.
" migraine ", " headache " and relational language are as the doctor understands.Migraine contains all types of migraine, comprises coventional type (common), traditional (classic), the type of gathering together (cluster), lightning class (fulgurating), hemiplegia type (hemiplegic), ophthalmoplegia type (opthalmoplegic) and opthomalmic.
" treatment effectively " is meant significant patient's benefit that the doctor understands.
" patient " is meant the determined people that have benefited from treating of doctor.
Embodiment
Abbreviation meets the usual meaning of this area usually.The chemical abbreviations of using in specification sheets and embodiment is as giving a definition: " NaHMDS " represents two (trimethyl silyl) sodium amide; " DMF " represents N, dinethylformamide; " MeOH " represents methyl alcohol; " NBS " expression N-bromine succinimide; " Ar " represents aryl; " TFA " represents trifluoroacetic acid; " LAH " represents lithium aluminium hydride; " BOC " expression tertbutyloxycarbonyl, " DMSO " represent dimethyl sulfoxide (DMSO); " h " expression hour; " rt " expression room temperature or retention time (depending on the circumstances); " min " expression minute; " EtOAc " represents ethyl acetate; " THF " represents tetrahydrofuran (THF); " EDTA " represents ethylenediamine tetraacetic acid (EDTA); " Et 2O " the expression ether; " DMAP " represents 4-dimethylaminopyridine; " DCE " expression 1, the 2-ethylene dichloride; " ACN " represents acetonitrile; " DME " expression 1, the 2-glycol dimethyl ether; " HOBt " expression I-hydroxybenzotriazole hydrate; " DIEA " represents diisopropyl ethyl amine, and " Nf " represents CF 3(CF 2) 3SO 2-; And " TMOF " represents trimethyl orthoformate.
Abbreviation used in this application is as giving a definition: " 1 * " represent once; Twice of " 2 * " expression; " 3 * " expression three times; " ℃ " expression degree centigrade; " eq " represents equivalent; " g " represents gram; " mg " represents milligram; " L " represents to rise; " mL " or " ml " represents milliliter; " μ L " represents microlitre; " N " represents equivalent concentration; " M " represents volumetric molar concentration; " mmol " represents mmole; " min " expression minute; " h " expression hour; " rt " represents room temperature; " RT " represents retention time; " atm " represents normal atmosphere; " psi " represents pound per square inch; " conc. " expression is dense; " sat " or " sat ' d " expression is saturated; " MW " represents molecular weight; " mp " represents fusing point; " ee " expression enantiomer is excessive; " MS " or " Mass Spec " represents mass spectrum; " ESI " expression electro-spray ionization mass spectrum; " HR " represents high resolving power; " HRMS " represents high resolution mass spec; " LCMS " represents liquid chromatography-mass spectrography; " HPLC " represents high performance liquid chromatography; " RP HPLC " represents reversed-phase HPLC; " TLC " or " tlc " represents thin-layer chromatography; " NMR " represents NMR (Nuclear Magnetic Resonance) spectrum; " 1H " the expression proton; " δ " represents Delta; " s " expression is unimodal; " d " represents doublet; " t " represents triplet; " q " represents quartet; " m " represents multiplet; " br " represents broad peak; " Hz " represents hertz; And the stereochemistry symbol be familiar with for those skilled in the art of " α ", " β ", " R ", " S ", " E " and " Z ".
Record proton resonance spectrum on Bruker AC300 or AC500 ( 1H NMR).All spectrum shown in determine that chemical shift is reported with the δ unit that is in low with respect to interior mark tetramethylsilane (TMS), and coupling constant is reported with hertz (Hz) between proton in the solvent.It is unimodal splitting the following appointment of merotype: s; D is a doublet; T is a triplet; Q is a quartet; M is a multiplet; Br is a broad peak.Low resolution mass spectrum (MS) and apparent molecular weight (MH+) or (M-H)+on Micromass Platform, determine.Ultimate analysis is reported with weight percentage.The following purifying of product: preparation property HPLC, (30 * 100mm), flow velocity is 40.0 ml/min, and the gradient time is 8.0 minutes, and solvent composition is with 40%MeOH-60%H to use chromatographic column YMC S5ODS 2O-0.1%TFA is initial, and solvent composition is with 95%MeOH-5%H 2O-0.1%TFA is for finishing.The following analysis of product: HPLC instrument, use XTERA chromatographic column (3.0 * 50mm S7), start from solvent orange 2 A (10%MeOH-90% water-0.1% trifluoroacetic acid (TFA)), and last gradient time of 2 minutes and reach solvent B (10% water-90% methyl alcohol-0.1%TFA).Flow velocity is 5 ml/min, and the retention time of product is measured with the wavelength of 220nm.
Intermediate 1
Figure BPA00001276869200281
4-iodine but-1-ene
The oven dry 500mL round-bottomed flask (t=g) in triphenylphosphine (22.40g, 85mmol) and imidazoles (5.82g is 85mmol) at CH 2Cl 2Solution (200mL) is cooled to 0 ℃, obtains colourless solution.Careful adding iodine (21.68g, 85mmol).After 15 minutes, (7.0mL 81mmol), and is warmed to ambient temperature overnight with mixture dropwise to add 3-butene-1-alcohol.With CH 2Cl 2Vacuum is removed but is not heated (product highly volatile! ), obtaining orange slurries, it dilutes with pentane and filters by Celite pad and layer of silica gel.Then the solvent vacuum is removed and do not carry out warm.Obtaining little yellow oil is thick 4-iodine but-1-ene (11.51g, 78%), and it is directly used in following reaction.
Intermediate 2
5-(2, the 3-difluorophenyl) ninth of the ten Heavenly Stems-1,8-diene-5-alcohol
In 500mL round-bottomed flask (t=g) to Et 2(11.51g 63.2mmol), obtains colourless solution to add thick 4-iodine but-1-ene among the O (100mL).After under nitrogen, being cooled to-78 ℃, via syringe dropwise add tBuLi (tert-butyl lithium) (80mL, 136mmol).Mixture slowly is warmed to room temperature to be stirred 2 hours simultaneously.After room temperature kept 20 minutes, mixture is cooled to-78 ℃ and dropwise add 2 via syringe, 3-difluoro-benzoic acid ethyl ester (4.28mL, 28.7mmol).Last 30 minutes mixture is warmed to room temperature gradually.The cancellation of reaction mixture water is also evaporated volatile matter.Residue is distributed between water and EtOAc.Separate each layer, Na is used in organic layer salt water washing 2SO 4Dry and concentrated, obtain faint yellow oily thing.Use 40%Et 2O/ hexane purifying obtains required product, and it is colorless oil (1.41g, 19%). 1H?NMR(400MHz，CDCl 3)δ7.31-7.22(m，1H)，7.10-7.03(m，2H)，5.82-5.70(m，2H)，4.97-4.85(m，4H)，2.20-2.00(m，4H)，2.00-1.75(m，4H)。
Intermediate 3
Figure BPA00001276869200291
(Z)-1-(2, the 3-difluorophenyl) ring heptan-4-enol
In 500mL round-bottomed flask (t=g) to CH 2Cl 2Add 5-(2, the 3-difluorophenyl) ninth of the ten Heavenly Stems-1 (50mL), (1.15g 4.56mmol), obtains colourless solution to 8-diene-5-alcohol.Add Grubbs II (0.193g, 0.228mmol), and with mixture 45 ℃ of heating 19 hours.TLC shows and significantly is converted into the bigger compound of polarity.Material and 68908-184 are merged, be concentrated into and do and residue 50%Et 2O/ hexane purifying.Merge main peak and concentrated, obtain colorless oil (0.761g, 74.5%). 1H NMR shows and most ofly to be required product (coming the synthetic compound identical with using Grubbs I catalyzer after a while), and accessory constituent has isomerized pair of key.
Intermediate 4
(Z)-5-(2, the 3-difluorophenyl) ring heptan-1-alkene
In 100mL round-bottomed flask (t=g) to CH 2Cl 2Add (16mL) that (Z)-1-(2, the 3-difluorophenyl) ring heptan-(872mg 3.89mmol), obtains colourless solution to the 4-enol.(3.11mL 19.44mmol), then adds TFA (8.00mL) to add triethyl-silicane.With mixture stirring at room 2.5 hours.TLC shows and significantly is converted into the less compound of polarity.It is concentrated and by FCC 20%Et 2O/ hexane purifying obtains required product, and it is colorless oil (769mg, 95%).Product is come out by quick wash-out. 1H NMR confirms described structure (main peak with the synthetic compound is identical after a while).
Intermediate 5
Figure BPA00001276869200293
5-(2, the 3-difluorophenyl)-2-hydroxyl suberone
Referring to Plietker, B.J.Org.Chem.2004,69,8287-8296).In 500mL round-bottomed flask (t=g) with stirring rod add sodium bicarbonate (827mg, 9.84mmol).Add ruthenium trichloride (III) (8.17mg, 0.039mmol) (in reference, use the aqueous solution but it is difficult to dissolve fully).In solid, add entry (3.94mL), EtOAc (20ml) and MeCN (acetonitrile) (20ml), obtain brown suspension.(1.21E+04mg 19.69mmol), forms the glassy yellow suspension to disposable adding potassium hydrogen peroxymonosulfate.Mixture is cooled to-20 ℃.Add that (Z)-5-(2, the 3-difluorophenyl) ring heptan-(820mg is 3.94mmol) (with EtOAc/MeCN (1/1,7.2ml) washing) for 1-alkene.Color becomes little tawny immediately.Reaction mixture was stirred 1.5 hours at-20 ℃ to-15 ℃.The TLC demonstration does not react.Be warmed to 0 ℃ and keep 10 minutes, do not have very big improvement but TLC shows reaction.It is warmed to room temperature and kept 15-20 minute.TLC show a less main spot of polarity disappear (less important spot reservation) and occur polarity bigger have the active spot of ultraviolet slightly.Wash with solid filtering and with EtOAc.Organic solution NaHSO 3Solution washing.Organic layer Na 2SO 4Dry and concentrated, obtain colorless oil.It is by FCC 5%MeOH/CH 2Cl 2Purifying.Merge the bigger peak of polarity and concentrated, obtain colorless oil (169mg, 18%).It is directly used in following protective reaction.
Embodiment 1
Figure BPA00001276869200301
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid 5-(2, the 3-difluorophenyl)-2-oxo suberyl ester
(22mg, 0.092mmol) (20.30mg 0.101mmol), obtains colourless solution with chloroformic acid 4-nitrophenyl ester to add 5-(2, the 3-difluorophenyl)-2-hydroxyl suberone in the 50mL round-bottomed flask (t=g) of oven dry in THF (3mL).Add DMAP (15.66mg, 0.128mmol), and with mixture stirring at room 3 hours.TLC shows the less new spot (polarity is bigger than above-mentioned muriate) of polarity but is mainly starting raw material.Reaction mixture is stirred spend the night (24 hours).In above-mentioned reaction mixture, add 1-(piperidin-4-yl)-1H-imidazo [4,5-b] pyridines-2 (3H)-ketone (53.6mg, 0.184mmol), then add Xu Nixi (Hunig ' s) alkali (0.040mL, 0.230mmol).With resulting mixture in stirred overnight at room temperature.LCMS shows two approaching small peaks, and its molecular weight is 484.22h: its dilute with water also extracts with EtOAc.Na is used in organic layer water and salt water washing 3 times 2SO 4Dry and concentrated, obtain tawny oily matter.Use 8%MeOH/CH 2Cl 2Carry out FCC, obtain required product, it is the mixture (11.7mg, 26%) of two kinds of diastereomers.LCMS：M+H＝485。
Intermediate 6
The ninth of the ten Heavenly Stems-1,8-diene-5-ketone
(6.04mL 54.7mmol), obtains brown solution to add the 4-prenyl chloride in the 500mL round-bottomed flask (t=g) of oven dry in THF (80mL).After being cooled to-78 ℃, last 90 minutes via syringe add 3-butenyl magnesium bromide (115mL, 57.5mmol).After being warmed to room temperature and keeping 3 hours, the saturated NH of reaction mixture 4The cancellation of Cl solution.THF is removed and residue extracts with EtOAc.Na is used in organic layer salt water washing 2SO 4Dry and concentrated, obtain little yellow oil.By FCC 40%Et 2O/ hexane purifying (two batches) obtains product, and it is colorless oil (5.13g, 68%). 1H?NMR(400MHz，CDCl 3)δ5.84-5.68(m，2H)，5.05-4.90(m，4H)，2.49(t，J＝7.4Hz，4H)，2.35-2.20(m，4H)。
Intermediate 7
5-(2, the 3-difluorophenyl) ninth of the ten Heavenly Stems-1,8-diene-5-alcohol
Add 1-bromo-2 in the 250mL round-bottomed flask (t=g) of oven dry in THF (60mL), (2.304mL 20.58mmol), obtains colourless solution to 3-two fluorobenzene.After being cooled to-78 ℃, via syringe dropwise add BuLi (butyllithium) (8.23mL, 20.58mmol).Mixture was stirred 20 minutes at-78 ℃, and dropwise add the ninth of the ten Heavenly Stems-1,8-diene-5-ketone (2.37g, 17.15mmol) (with the dry-out benzene azeotropic) (and using 6ml THF drip washing) via conduit.Last 1 hour mixture is warmed to room temperature.The water cancellation is also removed the THF solvent.Residual mixture extracts with EtOAc.Separate each layer, Na is used in organic layer salt water washing 2SO 4Dry and concentrated, obtain yellow oil.Residue is by FCC 35%Et 2O/ hexane purifying.Merge required cut and concentrated, obtain product, it is colorless oil (2.39g, 55.3%). 1HNMR(400MHz，CDCl 3)δ7.30-7.22(m，1H)，7.10-7.03(m，2H)，5.82-5.70(m，2H)，4.97-4.85(m，4H)，2.20-2.00(m，4H)，2.00-1.75(m，4H)。
Intermediate 8
Figure BPA00001276869200321
(Z)-1-(2, the 3-difluorophenyl) ring heptan-4-enol
In 1L round-bottomed flask (t=g) to CH 2Cl 2Add 5-(2, the 3-difluorophenyl) ninth of the ten Heavenly Stems-1 (600mL), (1.76g 6.98mmol), obtains colourless solution to 8-diene-5-alcohol.Add Grubbs I (0.175g, 0.209mmol), and with mixture 40 ℃ of heating 2 hours.TLC shows and significantly is converted into the bigger compound of polarity (some impurity are from residual starting raw material).Merge with 68908-198, be concentrated into and do and residue 50%Et 2O/ hexane purifying (twice).Merge main peak and concentrated, obtain light green oily matter (1.40g, 89.2%). 1H?NMR(400MHz，CDCl 3)δ7.34-7.25(m，1H)，7.08-7.00(m，2H)，5.90-5.80(m，2H)，2.60-2.48(m，2H)，2.21(t，J＝7.0Hz，2H)，2.10-1.98(m，2H)，1.90-1.75(m，2H)。
Intermediate 9
Figure BPA00001276869200322
(Z)-5-(2, the 3-difluorophenyl) ring heptan-1-alkene
In 250mL round-bottomed flask (t=g) to CH 2Cl 2Add (40mL) that (Z)-1-(2, the 3-difluorophenyl) ring heptan-(2.05g 9.14mmol), obtains colourless solution to the 4-enol.(7.30mL 45.7mmol), then adds TFA (20mL) to add triethyl-silicane.With mixture stirring at room 3 hours.TLC shows conversion (Rf=0.42 (pure hexane)) fully.It is concentrated, obtain double-deck oily matter (lower floor is insoluble in the hexane).Only use hexane to come purifying by FCC, obtain required product, it is colorless oil (1.684g, 88%). 1H?NMR(400MHz，CDCl 3)δ7.00-6.90(m，3H)，5.90-5.82(m，2H)，3.20-3.05(m，1H)，2.40-2.15(m，4H)，1.90-1.78(m，2H)，1.60-1.40(m，2H)。
Intermediate 10
Figure BPA00001276869200323
5-(2, the 3-difluorophenyl) suberane-1, the 2-glycol
Referring to D.A.Spiegel et al.Tetrahedron 2002,58,6545-6554.In 250mL round-bottomed flask (t=g), in acetone (9mL) and water (0.18mL), add (Z)-5-(2, the 3-difluorophenyl) ring heptan-1-alkene (1.249g, 6.00mmol) and NMO (1.546g 13.19mmol), obtains white suspension.Add perosmic anhydride (0.301mL, 0.024mmol) (concentration is 2-methyl-2-propanol solution of 2.5wt%).With mixture in stirring at room.Dissolving gradually that NMO lasts 30 minutes obtains yellow solution.The 1h:TLC demonstration is converted into the big compound of polarity fully.Add sodium bisulfite (200mg) and continue and stirred 30 minutes.Removing acetone and residue extracts three times with EtOAc.The organic layer salt water washing that merges, dry and concentrated, obtain white solid (big and heavy 1.7g).It is directly used in following reaction.
Intermediate 11
Figure BPA00001276869200331
2-(t-butyldimethylsilyl oxygen base)-5-(2, the 3-difluorophenyl) suberyl alcohol
Add 5-(2, the 3-difluorophenyl) suberane-1 in 250mL round-bottomed flask (t=g) in DMF (20mL), (1.454g, 6.0mmol) (with dry-out benzene azeotropic crude product) obtains colourless solution to the 2-glycol.Add TBS-Cl (0.995g, 6.60mmol) and imidazoles (0.980g, 14.40mmol), and with mixture stirring at room 5 hours.(2/1 hexane/EtOAc) shows and is converted into two kinds of main compound fully TLC.Its dilute with water is also used the EtOAc extracting twice.Na is used in the organic layer salt water washing that merges 2SO 4Dry and concentrated, obtain colorless oil.With 30%EtOAc/ hexane purifying, obtain single required product of protecting by FCC, it is a broad peak.Merge product cut and concentrated, obtain colorless oil (1.79g, 84% (two steps)). 1H?NMR(400MHz，CDCl 3)δ7.02-6.85(m，3H)，3.98-3.70(m，2H)，3.18-3.02(m，1H)，2.15-1.82(m，4H)，1.80-1.45(m，4H)，0.91(s，9H)，0.90(2s，6H)。
Intermediate 12 and intermediate 13
Figure BPA00001276869200332
(2R, 5R)-2-(t-butyldimethylsilyl oxygen base)-5-(2, the 3-difluorophenyl) suberone
In 250mL round-bottomed flask (t=g) to CH 2Cl 22-(t-butyldimethylsilyl oxygen base)-(1.73g 4.85mmol), obtains colourless solution to 5-(2, the 3-difluorophenyl) suberyl alcohol in adding (50mL).The high idodine of disposable adding Dai Si-Martin (Dess-Martin Periodinane) (2.264g, 5.34mmol), and with mixture in stirred overnight at room temperature.17h:TLC shows conversion fully.It uses Et 2O dilution and with the saturated Na of 40ml 2S 2O 3And Na 2HCO 3Solution (1/1 mixture) is handled and is become clarification (10 minutes) up to milky solution.Separate each layer and water layer Et 2The O extraction.Na is used in the organic layer salt water washing that merges 2SO 4Dry and concentrated, obtain colorless oil (the some of them solid is insoluble in the hexane).By FCC 40%Et 2O/ hexane purifying obtains two peaks.They are merged separately and concentrate.The less essential substance (978mg, 55%) of polarity is a colorless oil. 1H NMR (500MHz, CDCl 3) δ 7.02-6.90 (m, 3H), 4.34 (d, J=4.6Hz, 1H), 2.82-2.75 (m, 2H), 2.54-2.46 (m, 1H), 2.45-2.32 (m, 1H), 2.17-1.98 (m, 2H), 1.90-1.68 (m, 3H), 0.94 (s, 9H), 0.08 (s, 6H); 13CNMR (125MHz, CDCl 3) δ 213.4,150.7 (dd, J=247.6 and 13.4Hz), 147.8 (dd, J=245.7 and 13.4Hz), 137.5 (d, J=11.5Hz), 127.7,122.2,114.7 (d, J=17.3Hz), 79.0,40.0,39.2,33.2,30.7,29.4,25.8,18.2 ,-5.0.The minor materials that polarity is bigger is leaving standstill after fixing, obtains white solid (698mg, 39%).It confirms inverted stereo chemistry (anti-stereochemistry) relation with hexane recrystallization and X-ray analysis. 1H NMR (500MHz, CDCl 3) δ 7.10-6.97 (m, 2H), 6.97-6.90 (m, 1H), 4.34 (dd, J=3.0 and 9.7Hz, 1H), 3.04-2.94 (m, 1H), 2.80-2.70 (m, 1H), 2.62-2.50 (m, 1H), 2.18-1.72 (m, 6H), 0.90 (s, 9H), 0.10 (s, 3H), 0.06 (s, 3H); 13C NMR (125MHz, CDCl 3) δ 211.0,150.8 (dd, J=248.6 and 13.5Hz), 148.1 (dd, J=246.7 and 12.5Hz), 136.4 (d, J=11.5Hz), 124.2,122.3,115.1 (d, J=17.3Hz), 78.4,40.3,39.4,34.3,33.0,30.4,25.9,18.5 ,-4.5 ,-5.1.
Intermediate 14
Figure BPA00001276869200341
(6,9-is trans)-9-(t-butyldimethylsilyl oxygen base)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine also
In 25mL flask (t=g), in ethanol (4mL), add (2S, 5S)-2-(t-butyldimethylsilyl oxygen base)-(279mg 0.787mmol), obtains colourless solution to 5-(2, the 3-difluorophenyl) suberone.Add the sour sodium dihydrate of tetrachloro gold (III) (sodium tetrachloroaurate (III) dihydrate) (9.39mg, 0.024mmol) and propargyl amine (0.101mL, 1.574mmol).Reaction mixture was heated 5 hours at 80 ℃.After the tawny mixture was cooled to room temperature, it diluted with EtOAc, filtered by tampon and concentrated, and obtained tawny oily matter.Carry out FCC with the 20%EtOAc/ hexane, obtain required product [it is main peak (60.3mg, 20%)] and a small amount of starting raw material that reclaims. 1H?NMR(400MHz，CDCl 3)δ8.45-8.40(m，1H)，7.32-7.29(m，1H)，7.08-7.04(m，1H)，7.04-6.92(m，2H)，6.92-6.80(m，1H)，5.13-5.07(m，1H)，3.30-3.00(m，3H)，2.32-2.10(m，2H)，2.10-1.90(m，2H)，0.91(s，9H)，0.074(s，3H)，0.042(s，3H)。
Intermediate 15
Figure BPA00001276869200351
(6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
In 50mL round-bottomed flask (t=g), in THF (3mL), add (6R, 9R)-9-(t-butyldimethylsilyl oxygen base)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine (60.3mg also, 0.155mmol), obtain colourless solution.Add TBAF (0.310mL, 0.310mmol), and with mixture in stirred overnight at room temperature.19h:LCMS and TLC show conversion fully.Remove THF, residue dilutes with EtOAc, and Na is used in water and salt water washing 2SO 4Dry and concentrated, obtain tawny oily matter.Carry out FCC with the 30%EtOAc/ hexane, obtain a peak,, obtain white solid (35.7mg, 84%) its merging and concentrated.LCMS:[M+H]=276; 1H NMR (400MHz, CDCl 3) δ 8.42-8.40 (m, 1H), 7.47 (d, J=7.6Hz, 1H), 7.16 (dd, J=7.2 and 5.0Hz, 1H), 7.15-7.00 (m, 3H), 5.97 (broad peak, 1H), 4.88 (dd, J=11.6 and 1.6Hz, 1H), 3.19 (t, J=12.8Hz, 1H), 2.99-2.83 (m, 1H), 2.80 (d, J=14.4Hz, 1H), 2.38-2.23 (m, 1H), 2.23-2.05 (m, 2H), 1.69-1.50 (m, 1H); 13C NMR (125MHz, CDCl 3) δ 160.7,150.8 (d, J=247.4Hz), 148.1 (d, J=261.2Hz), 145.1,137.8,136.5 (d, J=12.3Hz), 133.6,124.2,122.4,122.1,115.1 (d, J=16.9Hz), 71.8,40.5,37.6,36.2,35.8.
Embodiment 2
Figure BPA00001276869200352
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also
In 100mL round-bottomed flask (t=g), in THF (3mL), add (6R, 9R)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol (22.2mg also, 0.081mmol) (with the dry-out benzene azeotropic) and 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid 4-nitrophenyl ester (93mg, 0.242mmol), obtain the tawny suspension.Disposable adding NaH (19.35mg, 0.806mmol) (excessive).Mixture stirred under room temperature and nitrogen spend the night.18h:LCMS shows conversion fully.Its water cancellation (is emitted gas! ) and extract with EtOAc.Separate each layer and water layer and extract (LCMS is presented at does not have product in the aqueous solution) with EtOAc.Na is used in the organic layer salt water washing that merges 2SO 4Dry and concentrated.By FCC 8%MeOH/CH 2Cl 2Purifying obtains product, and it is white solid (28.6mg, 68%).LCMS:[M+H]=520; 1H NMR (400MHz, CDCl 3) δ 10.5 (broad peak, 1H), 8.47 (d, J=3.6Hz, 1H), 8.07 (d, J=4.4Hz, 1H), 7.44 (broad peak, 2H), 7.15 (broad peak, 1H), 7.09-6.95 (m, 4H), 6.03 (d, J=10.8Hz, 1H), 4.77-4.52 (broad peak, 2H), and 4.52-4.30 (broad peak, 1H), 3.36 (t, J=12.6Hz, 1H), and 3.20-2.90 (m, 3H), 2.83 (d, J=14.4Hz, 1H), and 2.42-2.12 (m, 4H), 2.02-1.78 (m, 4H); 248 ℃ of mp.
Embodiment 3
Figure BPA00001276869200361
4-(2-oxo-4,5-dihydro-1H-benzo [d] [1,3] diaza
Figure BPA00001276869200362
-3 (2H)-yl) piperidines-1-carboxylic acid (6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also
In 100mL round-bottomed flask (t=g), in THF (2mL), add (6R, 9R)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol (13.5mg also, 0.049mmol) (with the dry-out benzene azeotropic) and 4-(2-oxo-4,5-dihydro-1H-benzo [d] [1,3] diaza
Figure BPA00001276869200363
-3 (2H)-yl) piperidines-(60.4mg 0.147mmol), obtains the tawny suspension to 1-carboxylic acid 4-nitrophenyl ester.Disposable adding NaH (11.77mg, 0.490mmol) (excessive).Mixture stirred under room temperature and nitrogen spend the night.18h:LCMS shows conversion fully.Its water cancellation (is emitted gas! ) and extract with EtOAc.Separate each layer and water layer extracts with EtOAc.Na is used in the organic layer salt water washing that merges 2SO 4Dry and concentrated.By FCC 8%MeOH/CH 2Cl 2Purifying obtains product, and it is a white powder.LCMS show secondary peaks (M+Br) but 1As if H NMR normal.Use NaHSO 3Solution-treated in MeOH/ water 2 days but do not improve.There is not recover materials (19.5mg, 73%) under the situation about changing.LCMS:[M+H]=547; 1H NMR (400MHz, CDCl 3) δ 8.41 (d, J=Hz, 1H), 7.39 (d, J=Hz, 1H), 7.12-6.95 (m, 5H), 6.88 (t, J=Hz, 1H), 6.72 (d, J=Hz, 1H), 6.65 (s, 1H), 5.98 (d, J=Hz, 1H), 4.60-4.18 (broad peak, 3H), 3.51 (broad peak, 2H), 3.33 (t, J=Hz, 1H), 3.15-2.89 (m, 6H), 2.82 (d, J=Hz, 1H), 2.32-2.10 (m, 3H), 2.05-1.89 (m, 1H), 1.89-1.55 (m, 4H).
Intermediate 16
Figure BPA00001276869200371
(6,9-is trans)-6-(2, the 3-difluorophenyl)-9-hydroxyl-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-1-oxide compound also
In the 250mL round-bottomed flask to CH 2Cl 2Add (6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8 (4mL), 9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol (191mg 0.694mmol), obtains colourless solution.Add mCPBA (metachloroperbenzoic acid) (202mg, 0.902mmol), and with mixture stirring at room 24 hours.LCMS shows and is converted into primary product fully.It is handled with the EtOAc dilution and with 0.5N NaOH.Separate each layer, Na is used in organic layer water and salt water washing 2SO 4Dry and concentrated, obtain waxy solid/oily matter (crude product: 100%).LCMS:[M+H]=292; 1H NMR (400MHz, CDCl 3) δ 8.06 (s, 1H), 7.24-6.40 (m, 5H), 5.27 (broad peak, 1H), 3.42-3.02 (m, 2H), 3.02-2.68 (m, 2H), 2.30-1.95 (m, 3H), 1.80-1.60 (m, 1H).
Intermediate 17
(6,9-is trans)-6-(2, the 3-difluorophenyl)-9-hydroxyl-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-2-formonitrile HCN also
In the 100mL round-bottomed flask to CH 2Cl 2Add thick (6,9-is trans)-6-(2, the 3-difluorophenyl)-9-hydroxyl-6,7,8 (4mL), 9-tetrahydrochysene-5H-ring heptan also [b] pyridine-1-oxide compound (0.202g, 0.694mmol) (with the dry-out benzene azeotropic) obtains colourless solution.The adding dimethylcarbamyl chloride (0.064mL, 0.694mmol).After 2 hours, (0.111mL 0.833mmol) and with mixture stirs spend the night (16 hours) under nitrogen to add trimethylsilyl cyanide.Add again dimethylcarbamyl chloride (0.064mL, 0.694mmol) and trimethylsilyl cyanide (0.111mL, 0.833mmol).With mixture heating up backflow (bathing temperature is 45 ℃) 22 hours.LCMS shows a plurality of peaks and only residual a small amount of starting raw material.It uses saturated NaHCO 3The solution cancellation also extracts with EtOAc.Separate each layer, organic layer salt water washing, dry and concentrated, obtain tawny oily matter.It is dissolved among the 4ml THF and (0.694mL 0.694mmol) handled 4 hours with TBAF.Water layer EtOAc aftertreatment obtains the tawny residue.With 80%EtOAc/ hexane purifying, obtain product by FCC, it is colorless solid (53mg, 23%).LCMS：[M+H]＝372； 1H?NMR(400MHz，CDCl 3)δ7.65-7.52(m，2H)，7.10-6.95(m，3H)，5.15(d，J＝4.0Hz，1H)，4.94(d，J＝11.6Hz，1H)，3.24(t，J＝12.8Hz，1H)，2.92-2.83(m，2H)，2.40-2.30(m，1H)，2.20-2.10(m，2H)，1.68-1.53(m，1H)。
Embodiment 4
Figure BPA00001276869200381
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6,9-is trans)-2-cyano group-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also
In the 100mL round-bottomed flask, in THF (2mL), add (6,9-is trans)-6-(2, the 3-difluorophenyl)-and 9-hydroxyl-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-2-formonitrile HCN (52.6mg also, 0.175mmol) (with the dry-out benzene azeotropic) and 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid 4-nitrophenyl ester (201mg, 0.525mmol), obtain the tawny suspension.Disposable adding NaH (42.0mg, 1.752mmol) (excessive).Mixture is stirred spend the night (16 hours) under room temperature and nitrogen.LCMS shows conversion fully.Its water cancellation (is emitted gas! ) and extract with EtOAc.Separate each layer, Na is used in organic layer salt water washing 2SO 4Dry and concentrated.By FCC 10%MeOH/CH 2Cl 2Purifying obtains product, and it is white powder (76mg, 72%).LCMS:[M+H]=545; 1H NMR (400MHz, CDCl 3) δ 8.07 (broad peak, 1H), 7.75-7.24 (m, 4H), 7.20-6.90 (m, 4H), 5.98 (d, J=11.2Hz, 1H), 4.83-4.20 (m, 3H), 3.40 (t, J=12.8Hz, 1H), 3.28-2.75 (m, 3H), 2.60-2.10 (m, 5H), 2.10-1.78 (m, 4H).
Intermediate] 8
Figure BPA00001276869200382
2-bromo-3-vinyl pyridine
Referring to Spivey, A.C.; Shukla, L.; Hayler, J.F.Org.Lett.2007,9,891-894.(22.75mL, (21.13g is in THF 59.1mmol) (450mL) suspension 59.1mmol) to be added to first base three phenyl phosphonium bromides with butyllithium at 0 ℃.Solution becomes orange, reaction mixture is risen to room temperature and kept 30 minutes, then it is cooled back to 0 ℃.(10g, 53.8mmol) solution in 50mL THF is added in the reaction soln with 2-bromopyridine-3-formaldehyde via conduit.Form throw out and reaction mixture is risen to room temperature.The color of reaction mixture becomes green grey.After for some time, the color of reaction mixture becomes orange once more.Reaction mixture is spent weekend in stirring at room.Most of solvent vacuum is removed and crude product is distributed between water and ether.Separate twice of extracted with diethyl ether of organic layer and water layer.Combined ether layer, dry (Na 2SO 4), filter and concentrate.Product obtains by quick post (with ethyl acetate/hexane (10%) wash-out), and it is yellow oil (8.78g, 89%).MS (ESI) [M+H +]=184.04; 1HNMR δ ppm (400MHz, the 8.21-8.29 of chloroform-d) (m, 1H) 7.78 (dd, J=7.68,1.89Hz, 1H) 7.20-7.28 (m, 1H) 6.96 (dd, J=17.37,11.08Hz, 1H) 5.72 (d, J=17.37Hz, 1H) 5.46 (d, J=11.08Hz, 1H).
Intermediate 19
Figure BPA00001276869200391
2-(penta-4-thiazolinyl)-3-vinyl pyridine
(4.151g, 22.56mmol) (with the dry-out benzene azeotropic) obtains colourless solution to add 2-bromo-3-vinyl pyridine in the 500mL round-bottomed flask in THF (40mL).Under nitrogen, add Pd (Ph 3P) 4(0.782g, 0.677mmol).Via syringe add 4-pentenyl zinc bromide (46mL 23.00mmol) stirs under nitrogen simultaneously, and with resulting dark mixture stirring at room 5 minutes.Be heated backflow (70 ℃) spend the night (4:00pm) then.17h:LCMS shows and is converted into required product fully.Remove THF.Reaction mixture NH 4The cancellation of Cl solution is also diluted with EtOAc.Separate each layer, organic layer salt water washing, dry and concentrated, obtain yellow oil.Carry out FCC with the 30%EtOAc/ hexane, obtain required product, it is colorless oil (2.54g, 65%).MS (ESI) [M+H +]=174; 1HNMR (400MHz, δ ppm 8.39 (dd, J=4.78,1.51Hz, 1H) 7.69 (dd of chloroform-d), J=7.81,1.76Hz, 1H) 7.07 (dd, J=7.81,4.78Hz, 1H) 6.89 (dd, J=17.37,11.08Hz, 1H) 5.80 (dddd, J=17.06,10.26,6.67,6.55Hz, 1H) 5.62 (d, J=17.37Hz, 1H) 5.34 (d, J=11.08Hz, 1H) 4.85-5.09 (m, 2H) 2.76-2.92 (m, 2H) 2.11 (q, J=7.13Hz, 2H) 1.67-1.83 (m, 2H); 13C NMR (101MHz, δ ppm 159.17 (s, 1C) 148.31 (s of chloroform-d), 1C) 138.38 (s, and 1C) 133.22 (s, 1C), 133.19 (s, 1C), 131.73 (s, 1C) 121.40 (s, 1C) 117.22 (s, 1C) 114.87 (s, 1C) 34.99 (s, 1C) 33.64 (s, and 1C) 28.60 (s, 1C).
Intermediate 20
Figure BPA00001276869200401
(Z)-8,9-dihydro-7H-ring heptan [b] pyridine also
(2.1g 12.12mmol), obtains colourless solution to add 2-(penta-4-thiazolinyl)-3-vinyl pyridine in the 2L round-bottomed flask in ether (4ml).Adding HCl (30mL, 60.0mmol), and with mixture stirring 5 minutes.With volatile matter evaporation, obtain colorless oil, with itself and dry-out benzene azeotropic, obtain white solid then.Then it is dissolved in CH 2Cl 2(1L) (use argon-degassed), obtain colourless solution.(0.515g 0.606mmol), and stirred mixture in 5 hours in 40 ℃ (oil bath) heating under nitrogen simultaneously to add Grubbs II.LCMS shows conversion fully (TLC shows the main spot of polarity less than starting raw material).Mixture is concentrated, obtain tawny oily matter.It is dissolved among the EtOAc, uses saturated NaHCO 3Na is used in solution (containing a small amount of 0.5N NaOH solution) and salt water washing 2SO 4Dry and concentrated, obtain tawny oily matter.Carry out FCC with the 40%EtOAc/ hexane, obtain required product, it is tawny oily matter (1.79g, 92%).MS (ESI) [M+H +]=146.06; 1H NMR (400MHz, δ ppm 8.20 (d, the J=4.78Hz of chloroform-d), 1H) 7.32 (d, J=7.55Hz, 1H) 6.99 (dd, J=7.55,5.04Hz, 1H) 6.21 (dt, J=12.28,2.05Hz, 1H) 5.90 (dt, J=12.34,4.41Hz, 1H) 2.93-3.06 (m, 2H) 2.30-2.49 (m, 2H) 1.82-2.02 (m, 2H); 13C NMR (101MHz, the δ ppm160.56 of chloroform-d) (s, 1C) 146.26 (s, 1C) 137.79 (s, 1C) 134.18 (s, 1C) 131.32 (s, 1C) 127.24 (s, 1C) 121.16 (s, 1C) 39.10 (s, 1C) 32.54 (s, and 1C) 24.87 (s, 1C).
Intermediate 21
Figure BPA00001276869200402
Acetate 6-bromo-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-5-base ester also
Under nitrogen, in the 500mL round-bottomed flask, in acetate (100mL), add (Z)-8,9-dihydro-7H-ring heptan also [b] pyridine (5.16g, 35.5mmol) and lithium acetate (9.38g 142mmol), obtains the tawny suspension.The adding N-bromoacetamide (5.00g, 36.2mmol).Flask coat with aluminium foil and with mixture in stirred overnight at room temperature.16h: no solid residue and LCMS demonstration are converted into the bigger required product of polarity (it is main peak) fully.Under high vacuum, remove AcOH.Residue water and EtOAc dilution.Add Na 2CO 3With neutralise mixt up to no longer emitting gas.Separate each layer and water layer extracts with EtOAc.Na is used in the organic layer salt water washing that merges 2SO 4Dry and concentrated, obtain stiff tawny oily matter (10.5g, 100%).Crude product in statu quo uses.MS(ESI)[M+H +]＝284.17。
Intermediate 22
Figure BPA00001276869200411
Acetate 6-bromo-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-5-base ester epoxide also
Add acetate 6-bromo-6,7,8 in the 500mL round-bottomed flask in THF (100mL), 9-tetrahydrochysene-5H-encircles heptan, and also [b] pyridine-(10.09g, 35.5mmol) (with the dry-out benzene azeotropic) obtains brown solution to 5-base ester.(9.59g 178mmol) and with mixture stirs under room temperature and nitrogen to add sodium methylate.The 2h:TLC demonstration is converted into the bigger product of polarity fully.2.5h: remove THF and residue is distributed between water and EtOAc.Water layer extracts with EtOAc.Na is used in the organic layer salt water washing that merges 2SO 4Dry and concentrated, obtain tawny oily matter (5.71g, 100%), it is directly used in following reaction.MS(ESI)[M+H +]＝162.21。
Intermediate 23
Figure BPA00001276869200412
6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-6-alcohol also
In the 500mL round-bottomed flask, in MeOH (100mL), add above-mentioned epoxide (5.72g, 35.5mmol) and Pd/C (1.889g 1.775mmol), obtains the black suspension.Is to stir 2 hours under the 1 atmospheric hydrogen (air bag) it at pressure.LCMS shows residual a small amount of starting raw material.Add 0.95g Pd/C again and continue again and stirred 1 hour.TLC shows not change (vestige may not be a starting raw material).With its filtration and concentrated, obtain tawny oily matter (6g, 100%).It need not to be further purified and characterizes and promptly is used for following reaction.
Intermediate 24
Figure BPA00001276869200413
8,9-dihydro-5H-ring heptan is [b] pyridine-6 (7H)-ketone also
Under-55 ℃ and nitrogen in the 500mL round-bottomed flask of oven dry to CH 2Cl 2(3.42mL 39.1mmol), obtains colourless solution to add oxalyl chloride (100mL).Last 10 minutes and dropwise add DMSO (5.54mL, 78mmol).With the solution restir after 30 minutes, last 5 minutes via conduit and add 6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-6-alcohol (5.79g, 35.5mmol) (with the dry-out benzene azeotropic) is at 20ml CH 2Cl 2In solution (and use 20ml drip washing).With reaction mixture at-50 ℃ to-55 ℃ restir 40 minutes (solution becomes emulsus).Add Et at-50 ℃ via syringe 3(24.74mL 178mmol) and with reaction mixture stirs 30 minutes (gel-like substance be difficult to stir and need in envrionment temperature jolting frequently) to N (triethylamine).Add 100ml water and separate each layer.Water layer CH 2Cl 2(2 * 100ml) extractions.The organic layer Na that merges 2SO 4Dry and concentrated, obtain tawny oily matter (containing some solids).By FCC 10%MeOH/CH 2Cl 2Purifying obtains required product, and it is orange (4.947g, 86% (4 step)). 1H NMR (500MHz, the δ ppm 8.28-8.38 of chloroform-d) (m, 1H) 7.37 (d, J=7.63Hz, 1H) 7.00-7.13 (m, 1H) 3.65 (s, 2H) 3.10-3.18 (m, 2H) 2.50-2.60 (m, 2H) 2.01 (dd, J=6.71,4.88Hz, 2H); 13C NMR (126MHz, the δ ppm 207.23 of chloroform-d) (s, 1C) 160.24 (s, 1C) 147.98 (s, 1C) 137.20 (s, 1C) 128.85 (s, 1C) 122.25 (s, 1C) 48.89 (s, 1C) 43.96 (s, 1C) 36.15 (s, and 1C) 24.70 (s, 1C).
Intermediate 25
Figure BPA00001276869200421
6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-6-alcohol also
Under-78 ℃ and nitrogen in the 500mL round-bottomed flask of oven dry to THF (100mL) in adding BuLi (17.19mL 43.0mmol), obtains colourless solution.Dropwise add 1-bromo-2 via syringe, and 3-two fluorobenzene (4.81mL, 43.0mmol).Mixture was stirred 20 minutes at-78 ℃, and dropwise add 8 via conduit, 9-dihydro-5H-ring heptan is [b] pyridine-6 (7H)-ketone (4.947g, 30.7mmol) (with the dry-out benzene azeotropic and dry under the high vacuum) solution in 10ml THF (and with 10ml THF drip washing) also.Last 1 hour mixture is warmed to room temperature.The TLC display part is converted into the big slightly compound of polarity.Use saturated NH 4After the cancellation of Cl solution, remove THF.Residual mixture is distributed between water and EtOAc.Separate each layer, Na is used in organic layer salt water washing 2SO 4Dry and concentrated, obtain dark oily matter.Residue is by FCC 10%MeOH/CH 2Cl 2Purifying (extremely difficult the separation).Merge impure cut and by FCC EtOAc/CH 2Cl 2To pure EtOAc purifying.The starting raw material that reclaims: 1.88g (38%).Merge product cut and concentrated, obtain the tawny solid, it uses Et 2The O repetitive scrubbing obtains tawny solid (1.79g, 21%). 1H NMR (400MHz, δ ppm 8.27 (dd, J=4.91, the 1.38Hz of chloroform-d), 1H) 7.38-7.47 (m, 1H) 7.30-7.35 (m, 1H) 6.97-7.12 (m, 3H) 3.93 (dd, J=14.60,2.52Hz, 1H) 3.06-3.20 (m, 2H) 2.86 (dd, J=14.60,1.76Hz, 1H) 2.37-2.68 (m, 2H) 1.68-1.94 (m, 2H) 1.17 (t, J=7.05Hz, 1H).
Intermediate 26 and 27
Figure BPA00001276869200431
(E)-and 6-(2, the 3-difluorophenyl)-8,9-dihydro-7H-ring heptan is [b] pyridine and (E)-6-(2, the 3-difluorophenyl)-8 also, and 9-dihydro-5H-ring heptan is [b] pyridine also
In the 250mL round-bottomed flask, add 6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-6-alcohol (1.23g, 4.47mmol) and HCl (20mL 6M solution 120mmol), and heats mixture 2 hours 100 ℃ (backflow).LCMS shows fully and significantly conversion.After being cooled to room temperature, it is with the EtOAc dilution and slowly with 15ml10N NaOH alkalization.Separate each layer, organic layer salt water washing, dry and concentrated, obtain tawny oily matter.Carry out FCC with the 80%EtOAc/ hexane, obtain main peaks (1) (0.71g) and secondary peaks (2) (90mg) and both some mixtures (0.34g).Amount to: 1.14g (97%: be about 75% and be about 22%) for 2 for 1. 1H NMR confirms both said structures.For (E)-6-(2, the 3-difluorophenyl)-8,9-dihydro-7H-ring heptan is [b] pyridine (1) also: 1HNMR (400MHz, the δ ppm 8.33 of chloroform-d) (dd, J=5.04,1.51Hz, 1H) 7.40-7.51 (m, 1H) 6.98-7.18 (m, 4H) 6.53 (s, 1H) 3.04-3.22 (m, 2H) 2.63 (t, J=6.55Hz, 2H) 2.17-2.32 (m, 2H).For (E)-6-(2, the 3-difluorophenyl)-8,9-dihydro-5H-ring heptan is [b] pyridine (2) also: 1H NMR (400MHz, the δ ppm 8.35 of chloroform-d) (dd, J=4.91,1.38Hz, 1H) 7.39 (d, J=7.55Hz, 1H) 6.81-7.10 (m, 4H) 5.67 (t, J=4.28Hz, 1H) 3.73 (s, 2H) 3.23-3.34 (m, 2H) 2.48-2.65 (m, 2H).
Intermediate 28
Figure BPA00001276869200432
6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine also
In the 250mL round-bottomed flask, in MeOH (4mL), add (E)-6-(2, the 3-difluorophenyl)-8,9-dihydro-5H-ring heptan also [b] pyridine (112mg 0.435mmol), obtains colourless solution.(46.3mg 0.044mmol), and stirs mixture 2 hours under the hydrogen air bag to add Pd/C.TLC shows that a main peak (it is a starting raw material) and LCMS had not only shown the starting raw material parent ion but also shown the precursor ion but both are co-elutes.Add 23mg Pd/C again and mixture is stirred spend the night (19 hours) under hydrogen.LCMS shows fully and transforms (unimodal corresponding to unique product: M+H=260).Wash with its filtration and with MeOH.With solution concentration, obtain colorless oil (106mg, 94%).Crude product 1H NMR confirms said structure and shows high purity. 1H NMR (400MHz, δ ppm 8.30 (dd, the J=4.78 of chloroform-d), 1.51Hz, 1H) 7.35 (dd, J=7.55,1.51Hz, 1H) 6.89-7.12 (m, 4H) 3.17-3.31 (m, 1H) 3.01-3.17 (m, 2H) 2.88-3.00 (m, 1H) 2.74 (d, J=14.10Hz, 1H) 2.01-2.19 (m, 2H) 1.85-2.01 (m, 1H) 1.46-1.70 (m, 1H).
Intermediate 29 and 30
Figure BPA00001276869200441
Racemic trans-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is the pure and mild cis-6-of [b] pyridine-9-(2, the 3-difluorophenyl)-6,7,8 also, 9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
In the 100mL round-bottomed flask to CH 2Cl 2Add 6-(2, the 3-difluorophenyl)-6,7,8 (4ml), 9-tetrahydrochysene-5H-ring heptan also [b] pyridine (106mg 0.409mmol), obtains colourless solution.Add mCPBA (137mg, 0.613mmol) and with resulting solution in stirred overnight at room temperature.19h:LCMS shows and is converted into the N-oxide compound fully.Mixture is with EtOAc dilution and with 1N NaOH solution washing.Na is used in organic layer salt water washing 2SO 4Drying, and vacuum concentration obtain white solid.It need not to be further purified and characterizes and promptly is used for following reaction.MS(ESI)[M+H +]＝276.13。
In the 100mL round-bottomed flask to CH 2Cl 2Add 6-(2, the 3-difluorophenyl)-6,7,8 (4mL), 9-tetrahydrochysene-5H-ring heptan also [b] pyridine-1-oxide compound (113mg, 0.409mmol) (faint yellow oily thing and with dry-out benzene azeotropic) obtains yellow solution.After being cooled to 0 ℃, add TFAA (0.144mL, 1.023mmol) and with mixture stirring at room 4 hours.LCMS shows that required product only is 10% and is mainly starting raw material (maybe may be the N-oxide compound (slowly reset) of acidylate).Add 0.15ml TFAA again and with mixture in stirred overnight at room temperature.LCMS shows improvement slightly.Mixture was refluxed 4 hours and not improvement of reaction at 45 ℃.Remove volatile matter, add the 2ml diacetyl oxide and with mixture 130 ℃ (pre-warmed bath) heating 1.5 hours.LCMS shows no starting raw material.Dilute with its cooling and with EtOAc.With NaOH solution alkalization and separate each layer.Organic layer washes with water and concentrates, and obtains tawny oily matter.Then it is dissolved among the 2ml THF and and handled 1 hour with 1.5ml 1N NaOH.LCMS shows a main peak (it is required product) (M+H=276).Mixture is distributed between EtOAc and water.Separate organic layer, use the salt water washing, dry and concentrated, obtain tawny oily matter.By FCC 50%EtOAc/ hexane purifying, obtaining two compounds (being very approaching spot on TLC) is a and b.With the further wash-out of 80%EtOAc/ hexane, obtain the bigger peak of polarity (it is c).As 1Shown in the H NMR, a is required trans alcohol (32.3mg, 29%) (analytical data is with previous described identical); B is dewatered product (10.4mg, 9.9%); And c is above-mentioned cis-alcohol (36mg, 32%).The polarity of cis-alcohol is than the polarity big a lot (with regard to the 50%EtOAc/ hexane, the Rf=0.16 of cis and trans Rf=0.77) of trans alcohol.Cis-alcohol 1H NMR: 1H NMR (500MHz, δ ppm 8.26 (d, J=4.58Hz, 1H) 7.30 (d of chloroform-d), J=7.63Hz, 1H) 7.04 (dd, J=7.32,4.88Hz, 1H) 6.85-6.98 (m, 2H) 6.79 (1H) 5.37 is (wide unimodal for t, J=6.87Hz, 1H) 5.01 (dd, J=7.17,3.81Hz, 1H) 3.28-3.52 (m, 2H) 2.93 (d, J=13.73Hz, 1H) 2.17-2.33 (m, 1H) 1.89-2.15 (m, 3H).
Intermediate 31
Figure BPA00001276869200451
(E)-and 6-(2, the 3-difluorophenyl)-8,9-dihydro-7H-ring heptan is [b] pyridine-9-alcohol also
In the 250mL round-bottomed flask to CH 2Cl 2Add (E)-6-(2, the 3-difluorophenyl)-8 (15ml), 9-dihydro-7H-ring heptan also [b] pyridine (546mg 2.122mmol), obtains colourless solution.Add mCPBA (571mg, 2.55mmol) and with resulting solution in stirred overnight at room temperature.4h:LCMS shows only residual trace starting raw material.21h: mixture is with EtOAc dilution and with 1N NaOH solution washing.Na is used in organic layer water and salt water washing 2SO 4Dry also vacuum concentration obtains stiff oily matter (100%).It need not to be further purified and characterizes and promptly is used for following reaction.MS(ESI)[M+H +]＝274.19。Referring to Kaiser, S.; Smidt, S.P.; Pfaltz, A.Angew.Chem.Int.Ed.2006,45,5194-5197.In the 100mL round-bottomed flask to CH 2Cl 2Add (E)-6-(2, the 3-difluorophenyl)-8 (16mL), 9-dihydro-7H-ring heptan also [b] pyridine-1-oxide compound (0.580g, 2.122mmol) (with the dry-out benzene azeotropic) obtains colourless solution.After being cooled to 0 ℃, add TFAA (0.749mL, 5.31mmol) and with mixture stirring at room 4 hours.Be placed in the refrigerator and spend weekend.(6.37mL 6.37mmol) and with mixture stirred 2 hours to add LiOH.It is with the dilution of EtOAc and water and separate each layer.Organic layer salt water washing, dry and concentrated, obtain tawny oily matter.With 50%EtOAc/ hexane purifying, obtain product by FCC, it is little yellow oil/solid (0.4g, 69% (2 step)).MS (ESI) [M+H +]=274.19; 1H NMR (400MHz, δ ppm8.36 (dd, J=4.78,1.51Hz, 1H) 7.50 (dd of chloroform-d), J=7.81,1.26Hz, 1H) 7.20 (dd, J=7.68,4.91Hz, 1H) 6.96-7.11 (m, 3H) 6.44 (s, 1H) 5.63 (broad peaks, 1H) 4.77 (dd, J=10.45,2.64Hz, 1H) 2.78-2.95 (m, 1H) 2.64-2.77 (m, 1H) 2.44-2.62 (m, J=13.60,5.48,5.48,2.64Hz, 1H) 1.92-2.15 (m, 1H); 13C NMR (101MHz, δ ppm 158.49 (s, 1C) 149.39-152.62 (m of chloroform-d), 1C) 146.03-149.25 (m, 1C) 145.24 (s, 1C) 143.70 (s, 1C) 139.94 (s, 1C) 138.79 (s, 1C) 134.46 (d, J=10.79Hz, 1C) 128.51 (d, J=11.56Hz, and 1C) 124.37 (wide unimodal, 1C) 123.81-124.14 (m, 1C) 122.44 (s, 1C) 116.24 (d, J=16.95Hz, 1C) 71.49 (s, 1C) 34.88 (s, 1C) 32.74 (d, J=3.08Hz, 1C).
Intermediate 32 and 33
Figure BPA00001276869200461
Racemic trans-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is the pure and mild cis-6-of [b] pyridine-9-(2, the 3-difluorophenyl)-6,7,8 also, 9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
In the 500mL round-bottomed flask, in MeOH (20mL), add (E)-6-(2, the 3-difluorophenyl)-8,9-dihydro-7H-ring heptan also [b] pyridine-9-alcohol (660mg 2.415mmol), obtains colourless solution.(257mg 0.242mmol), and stirs mixture 4 hours under the hydrogen air bag to add Pd/C.LCMS shows conversion fully.Filter and concentrate, obtain colorless oil.By FCC 80%EtOAc/ hexane purifying, obtaining two kinds of products is trans alcohol (104.3mg, 16%) and cis-alcohol (492.8mg, 74%), and both are white solid.The analytical data of these two kinds of alcohol is with previous described consistent.
Intermediate 34
Racemic (6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
In the 100mL round-bottomed flask, in THF (15mL), add (6, the 9-cis)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol (489mg, 1.776mmol) (with the dry-out benzene azeotropic) obtains colourless solution.Add the 4-nitrobenzoic acid (594mg, 3.55mmol) and Ph 3(932mg 3.55mmol), and is cooled to 0 ℃ with mixture to P.Dropwise add the diisopropyl azo-2-carboxylic acid (0.699mL, 3.55mmol).Mixture is warmed to room temperature and stirred 5 hours.LCMS shows and is converted into required intermediate and a small amount of dewatered product fully.Its stirring is spent the night and not change of LCMS demonstration.Add LiOH (8.88mL, 8.88mmol), and with mixture stirring at room 3 hours.LCMS shows that intermediate is converted into product fully.Remove THF and residue is distributed between EtOAc and 0.2N NaOH.Separate each layer, organic layer salt water washing, dry and concentrated, obtain little tawny oily matter.Carry out FCC with the 50%EtOAc/ hexane, obtain required product (378mg, 77%), it is a white solid.Analytical data is with previous described consistent.
Intermediate 35
Figure BPA00001276869200471
Triisopropyl (1-(2-ethenylphenyl) penta-4-thiazolinyl oxygen base) silicomethane
(2.8146g 15.38mmol) with dry-out benzene azeotropic twice, is absorbed among the THF (50ml) 1-bromo-2-vinyl benzene then.Solution is cooled to-78 ℃.(6.77ml 16.91mmol) is added in the reaction mixture and stirred 20 minutes in this temperature with BuLi at-78 ℃.(1.670ml 16.91mmol) is added in the reaction mixture and stirs and bathed temperature in 4 hours simultaneously and raise gradually with penta 4-olefine aldehydr.(3.58ml 16.91mmol) is added in the reaction mixture and reaction mixture is stirred to spend the night and simultaneously reaction mixture is warmed to room temperature with chlorine triisopropyl silicomethane.Vacuum is removed most of solvent and crude product is distributed between ethyl acetate and water.The separating ethyl acetate layer, dry (Na 2SO 4), filter and concentrate.Product comes purifying (with 0 to 30% ether/hexane wash-out) (3.9g, 74% yield) by the flash chromatography post.MS(ESI)[M+H +]＝346.46。
Intermediate 36
Figure BPA00001276869200472
(Z)-and 9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan is [b] pyridine also
(5.64mL, 11.28mmol) (10mL concentration is the diethyl ether solution of 2M) is added to 2-(1-(triisopropyl silyl oxygen base) penta-4-thiazolinyl)-3-vinyl pyridine (3.9g, CH 11.28mmol) with hydrogenchloride 2Cl 2(25mL) in the solution.Solvent removed in vacuo and corresponding twice of benzene azeotropic of hydrochloride.In reaction mixture, add CH 2Cl 2(500mL) and with nitrogen purge 10 minutes, add then GrubbII (0.192g, 0.226mmol).Reaction mixture is heated to 40 ℃ and kept 3 hours, and LCMS shows that no starting raw material is residual.The saturated NaHCO of reaction mixture 3Solution washing once.Separation of C H 2Cl 2, dry (Na 2SO 4), filter and concentrate.Carry out flash chromatography post (0 to 25% ether/hexane), obtain required product, it is yellow oil (2.54g, 71% yield).MS(ESI)[M+H +]＝318.35。
Intermediate 37
Figure BPA00001276869200481
Acetate 6-bromo-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-5-base ester also
Under room temperature and nitrogen with N-bromoacetamide (2.021g, 14.65mmol) be added to (Z)-9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan also [b] pyridine (4.5597g, 14.36mmol) and lithium acetate (3.79g is in AcOH 57.4mmol) (100mL) suspension.Flask is with the aluminium foil coating and in stirred overnight at room temperature.Reaction mixture becomes clear yellow solution.Solvent evaporates by high vacuum.Crude product is distributed between water and ethyl acetate.Add Na 2CO 3Up to no longer bubbling.Separating organic layer and water layer extracts once more with ethyl acetate.With the organic layer drying (Na that merges 2SO 4), filter and concentrate, obtain tawny oily matter (crude product is 6.37g).Crude product in statu quo uses.MS(ESI)[M+H +]＝458.36。
Intermediate 38
Acetate 6-bromo-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-5-base ester epoxide also
(3.77g 69.8mmol) is added to acetate 6-bromo-9-(triisopropyl silyl oxygen base)-6,7,8, and 9-tetrahydrochysene-5H-encircles heptan, and also [b] pyridine-(6.37g is in THF 13.95mmol) (100mL) solution for 5-base ester with sodium methylate under room temperature and nitrogen.Reaction mixture was stirred 2 hours.TLC shows that no starting raw material and product are the bigger spot of polarity with respect to starting raw material.The solvent vacuum is removed and crude product is distributed between ethyl acetate and water.Water layer extracts once more with ethyl acetate.With the organic layer drying (Na that merges 2SO 4), filter and concentrate, obtain crude product, it is tawny oily matter (crude product is 4.22g and 91%).MS(ESI)[M+H +]＝334.30。
Intermediate 39
Figure BPA00001276869200491
9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-6-alcohol also
Above-mentioned epoxide (4.22g, 12.65mmol) and palladium/charcoal (0.45g, 0.423mmol) mixture in MeOH (100mL) in room temperature with hydrogen air bag hydrogenation 2 hours.TLC shows that no starting raw material and required product are the bigger spot of polarity.Filter reaction mixture by silicagel pad and use methanol wash.Filtrate is concentrated, obtain required product, it is tawny oily matter (crude product is 4.1g and 97%).MS(ESI)[M+H +]＝336.37。
Intermediate 40
Figure BPA00001276869200492
9-(triisopropyl silyl oxygen base)-8,9-dihydro-5H-ring heptan is [b] pyridine-6 (7H)-ketone also
Under nitrogen, in the 500mL of oven drying round-bottomed flask, add oxalyl chloride (6.49mL, 72.9mmol) and CH 2Cl 2(150mL).Flask is cooled to-60 ℃ and with DMSO (6.90mL 97mmol) dropwise is added in the reaction mixture.After adding, reaction mixture was stirred 30 minutes at-60 ℃, then-60 ℃ via conduit with 9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-6-alcohol (8.1557g 24.31mmol) (is dissolved in 20mL CH 2Cl 2In and use 20mLCH 2Cl 2Drip washing) be added in the reaction mixture.Reaction mixture was stirred 40 minutes at-55 ℃, add then TEA (16.94mL, 122mmol).As if reaction mixture become the stiff suspension.Reaction mixture was stirred 1 hour and water is added in the reaction mixture.Separate organic layer and water layer CH 2Cl 2Extracting twice.Merge CH 2Cl 2Layer, dry (Na 2SO 4), filter and concentrate.Carry out flash chromatography post (25% to 50% ethyl acetate/hexane), obtain product, it is yellow oil (1.49g, 18.4%).MS (ESI) [M+H +]=334.30; 1H NMR (400MHz, δ ppm 8.36 (d, J=5.04Hz, 1H) 7.46 (d, the J=7.55Hz of chloroform-d), 1H) 7.16 (dd, J=7.55,4.78Hz, 1H) 5.22 (dd, J=4.78,2.27Hz, 1H) 4.66 (d, J=14.35Hz, 1H) 3.26 (d, J=14.60Hz, 1H) 2.94-3.05 (m, 1H) 2.42-2.55 (m, 1H) 2.36 (dd, J=14.10,5.04Hz, 1H) 2.03-2.17 (m, 1H) 1.03-1.16 (m, 3H) 0.96-1.00 (m, 9H) 0.89-0.92 (m, 9H).
Intermediate 41
Figure BPA00001276869200501
Trifluoromethanesulfonic acid (E)-9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan is [b] pyridine-6-base ester also
At-78 ℃ with LDA (3.73mL, 7.45mmol) be added to DMPU (2.073mL, 17.20mmol) and 9-(triisopropyl silyl oxygen base)-8,9-dihydro-5H-ring heptan also [b] pyridine-6 (7H)-ketone (1.9119g is in THF 5.73mmol) (25mL) solution.Reaction mixture was stirred 2 hours in this temperature, add 1,1 then, and 1-three fluoro-N-phenyl-N-(trifluoromethyl sulfonyl) Toluidrins (2.66g, 7.45mmol).Reaction mixture stirred to spend the night simultaneously it is warmed to room temperature gradually.The solvent vacuum is removed and crude product is loaded on (with 0% to 15% to 25% ethyl acetate/hexane wash-out) on the flash chromatography post, obtain required product (2.3g, 86%).MS (ESI) [M+H +]=466.33; 1H NMR (400MHz, δ ppm8.37 (dd, J=4.78, the 1.51Hz of chloroform-d), 1H) 7.47-7.54 (m, 1H) 7.20 (dd, J=7.81,4.78Hz, 1H) 6.43 (d, J=2.01Hz, 1H) 5.26 (d, J=7.55Hz, 1H) 3.16-3.32 (m, 1H) 2.58-2.69 (m, 1H) 2.29-2.39 (m, 1H) 1.85-1.98 (m, 1H) 1.01-1.09 (m, 3H) 0.93-1.00 (m, 9H) 0.85 (d, J=7.05Hz, 9H).
Intermediate 42
Figure BPA00001276869200502
(E)-and 6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan is [b] pyridine also
With 2,3-difluorophenyl boric acid (0.936g, 5.93mmol), yellow soda ash (4.57mL, 9.14mmol), trifluoromethanesulfonic acid (E)-9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan is [b] pyridine-6-base ester (2.3g also, 4.94mmol) and tetrakis triphenylphosphine palladium (0) (0.285g, 0.247mmol) mixture in toluene (30mL) and MeOH (6mL) is heated to 80 ℃ and kept 3 hours under nitrogen.LCMS shows no starting raw material.Reaction mixture dilutes with ethyl acetate and washes with water once.The separating ethyl acetate layer, dry (Na 2SO 4), filter and concentrate.Carry out flash chromatography post (0 to 25% ethyl acetate/hexane), obtain required product (0.8797g, 54%).MS(ESI)[M+H +]＝430.43。
Intermediate 43
Figure BPA00001276869200511
(E)-and 6-(2, the 3-difluorophenyl)-8,9-dihydro-7H-ring heptan is [b] pyridine-9-alcohol also
With (E)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan also [b] pyridine (1.6072g, 3.74mmol) and TBAF (7.48mL, 7.48mmol) mixture in THF (10mL) was stirring at room 1 hour.LCMS shows no starting raw material and is converted into required product.Solvent removed in vacuo.Reaction mixture comes purifying (with 0% to 35% to 50% ethyl acetate/hexane wash-out) by the flash chromatography post, obtains required product.It is white solid (0.825g, 81%).All analytical data are with previous described consistent.
Intermediate 44
Figure BPA00001276869200512
(R)-and 9-hydroxyl-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-5-ketone also
In the 1L round-bottomed flask, in THF (300mL), add (S)-9-hydroxyl-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-5-ketone (19.14g 108mmol) (also obtained by above-mentioned diketone is carried out enzyme) originally, obtained greenish orange look solution.Under nitrogen, add the 4-nitrobenzoic acid (27.1g, 162mmol) and Ph 3(42.5g 162mmol), and is cooled to 0 ℃ with mixture to P.Dropwise add the diisopropyl azo-2-carboxylic acid (31.9mL, 162mmol).Mixture is warmed to room temperature gradually and stirs spend the night (5:00pm).Color becomes tawny.15h:LCMS shows conversion fully.Add 80ml water, then add LiOH (7.76g, 324mmol).With mixture in stirring at room 2 hours (some LiOH are dissolving fully).2h:LCMS shows conversion (product/dewatered product is about 7/1 (passing through integration)) fully.Remove THF and the slowly acidifying of 40ml concentrated hydrochloric acid (12N) of residual mixture.Add 300ml EtOAc.With mixture jolting in the 1L separating funnel (adding the 10ml hexane) to promote separation.Separate (2 * 50mL) extractions of each layer and organic layer water.(4 * 100mL) wash the water layer that merges with EtOAc.The tawny aqueous solution slowly alkalizes with 50mL 10N NaOH then, and (4 * 150mL) extract with EtOAc.Water layer with NaCl saturated and with EtOAc (2 * 100mL) extract.The tawny organic layer (TLC demonstrates required product, dewatered product and some baselines) that merges is used the salt water washing, and is dry and concentrated, obtains tawny oily matter (crude product is 19.24g and 100%), and it is directly used in following steps.MS(ESI)[M+H +]＝178.24。
Intermediate 45
Figure BPA00001276869200521
(R)-and 9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-5-ketone also
In the 1L round-bottomed flask to CH 2Cl 2Add (R)-9-hydroxyl-6,7,8 (300mL), 9-tetrahydrochysene-5H-ring heptan also [b] pyridine-5-ketone (19.14g, 108mmol) (with the dry-out benzene azeotropic) obtains brown solution.After being cooled to 0 ℃, via syringe add TIPS-OTf (29.3mL, 108mmol) and Et 3(30.1mL 216mmol), and stirs mixture 1 hour at 0 ℃ N.LCMS shows conversion fully.Remove volatile matter and with residue at NaHCO 3Distribute between solution and the EtOAc.Separate each layer, organic layer salt water washing, dry and concentrated, obtain tawny oily matter (37g).It with 20%EtOAc/ hexane purifying, obtains product by FCC, and it is white solid (26.3g, 73% (two step)).MS(ESI)[M+H +]＝334.37。
Intermediate 46
Figure BPA00001276869200522
(6S, 9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-5-ketone also
Referring to Fox, J.M.; Huang, X.; Chieffi, A.; Buchwald, S.L.J.Am.Chem.Soc.2000,122,1360-1370.The oven dry the 1L flask in the nitrogen air bag weighing sodium tert-butoxide (13.19g, 137mmol), palladium diacetate (II) (0.948g, 4.22mmol) and 2-(dicyclohexyl phosphino-)-2 '-methyl diphenyl (1.539g, 4.22mmol).Under nitrogen, add (R)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-5-ketone (35.21g also, 106mmol), toluene (106mL) (in initial bottle, outgasing) and 1-bromo-2 with nitrogen, 3-two fluorobenzene (14.18mL, 127mmol).In the oil bath of preheating, flask was stirred 20 hours at 80 ℃.Remove volatile matter and residue is distributed between EtOAc (400ml) and water (400ml).Separate each layer.Water layer extracts with EtOAc (50ml).The organic layer salt water washing that merges, dry and concentrated, obtain dark oily matter.Its filtration (is used CH by silicagel pad 2Cl 2Load and with 30%EtOAc/ hexane wash-out).Obtain crude product, it is scarlet oily matter (86% mass yield). 1H NMR shows that the ratio of required trans-isomer(ide) and cis-isomeride is about 6/1.MS(ESI)[M+H +]＝446.21。
Intermediate 47
Figure BPA00001276869200531
(6R, 9R)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
In the 250mL round-bottomed flask, in MeOH (50mL), add (9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-5-ketone (9.59g 21.52mmol), obtains yellow solution.Add NaBH 4(1.628g, 43.0mmol), and with mixture stirring at room 40 minutes.LCMS shows conversion (main peaks of isomer and secondary peaks) fully.1h: vacuum is removed MeOH and residue is distributed between water and EtOAc.Separate each layer.Organic layer salt water washing, dry and concentrated, obtain light color oily matter (9.63g, 100%).MS(ESI)[M+H +]＝448.40。In the 500mL round-bottomed flask to CH 2Cl 2Add (9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8 (100mL), 9-tetrahydrochysene-5H-ring heptan also [b] pyridine-5-alcohol (9.63g, 21.52mmol) (with the dry-out benzene azeotropic) obtains yellow solution.After in ice bath, being cooled to 0 ℃, under nitrogen via syringe slowly add Ms-Cl (1.845mL, 23.67mmol) and Et 3N (9.00mL, 64.6mmol).After 30 minutes, remove cooling bath, and with mixture in stirring at room 2 hours (color becomes little red tawny).LCMS shows conversion fully.Remove desolvate and with residue at NaHCO 3Distribute between solution and the EtOAc (150ml).Separate each layer.Organic layer salt water washing, dry and concentrated, obtain yellow oil, and dried overnight (10.82g, 96%).MS(ESI)[M+H +]＝526.28。In the 500mL round-bottomed flask, in THF (100mL), add methylsulfonic acid (9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-encircles heptan, and also [b] pyridine-(11.31g 21.52mmol), obtains yellow solution to 5-base ester.Under nitrogen via syringe slowly add LAH (16.14mL, 32.3mmol) (concentration is the THF solution of 2M), and with mixture in stirring at room 1 hour (color becomes redness).LCMS shows conversion fully.Add anhydrous Na 2SO 4And the slow cancellation of reaction mixture water.Form gel.Filtrate and water-based aftertreatment fluid are merged, obtain faint yellow oily thing.By FCC 70%EtOAc/ hexane purifying, obtaining first peak is required product, and it is stiff tawny oily matter (being 1.44g and 24% after dry 4 days), described oily matter 1H NMR is consistent with above-mentioned racemic modification with HPLC/LCMS.Recyclable up to 22% various hydrolysis glycol.
Intermediate 48
Figure BPA00001276869200541
(9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-5-alcohol also for 5S, 6S
In the 1L round-bottomed flask, in cyclopentyl-methyl ether (400mL), add (9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-5-ketone (48g 108mmol), obtains brown solution.Be cooled to-15 ℃ in ice-MeOH bathes after, (9.39g 431mmol), lasts 4 hours with mixture (non-homogeneous) and is warmed to 10 ℃ and stirring at room 30 minutes gradually to add lithium borohydride.LCMS shows that conversion is fine.It is with the slow cancellation of 30ml MeOH and remove most of volatile matter under high vacuum.Residue dilutes with EtOAc and the slow cancellation of water under fully stirring.With mixture in stirred overnight at room temperature.Separate each layer.Dark organic layer salt water washing, dry and concentrated, obtain dark oily matter (48g, 100%).It is directly used in following reaction.MS(ESI)[M+H +]＝448.14。
Intermediate 49
Figure BPA00001276869200542
(9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-5-base ester also for 5S, 6S for methylsulfonic acid
In the 1L round-bottomed flask to C 6H 5CF 3Add (500mL) (5S, 6S, 9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-5-alcohol (47.17g, 105mmol) (with the dry-out benzene azeotropic) obtains brown solution.Under 0 ℃ and nitrogen with dropping funnel successively add Ms-Cl (24.63mL, 316mmol) and Et 3N (73.4mL, 527mmol) (11:00am).Dropwise add Et 3Behind the N, with suspension stirring at room 2 hours.LCMS mainly demonstrates precursor ion (overlapping with starting raw material in LCMS).Remove and desolvate and residue NaHCO 3Solution (300ml) is slowly handled.Add EtOAc (400ml).Separating each layer and water layer extracts with EtOAc (100ml).The organic layer salt water washing that merges, dry and concentrated, obtain tawny oily matter, it need not to be further purified and characterizes and promptly is used for following reaction.MS(ESI)[M+H +]＝526.14。
Intermediate 50
Figure BPA00001276869200551
(6R, 9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine also
In the 2L flask, in THF (300mL), add methylsulfonic acid (5S, 6S, 9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-encircles heptan, and also [b] pyridine-(55.2g, 105mmol) (with the dry-out benzene azeotropic) obtains brown solution to 5-base ester.Under nitrogen via dropping funnel dropwise add triethyl lithium borohydride (Superhydride) (525mL, 525mmol) (concentration is the THF solution of 1.0M), and with mixture stirring at room 4 hours.Remove THF and tawny oily matter is distributed between water (300ml) and EtOAc (400ml).Separate each layer, organic layer salt water washing, dry and concentrated, obtain tawny oily matter (about 60g).With 30%EtOAc/ hexane purifying, can not realize good purifying by FCC (2.5L packed column), but remove baseline (no good ultraviolet activity) impurity (only using silica gel plug and＜10%EtOAc/ hexane also can realize).The little polarity cut of all collections is merged and concentrate, obtain tawny oily matter (33.58g), it is directly used in following steps.MS(ESI)[M+H +]＝432.19。
Intermediate 51
Figure BPA00001276869200552
(6R, 9R)-6-(2, the 3-difluorophenyl)-6,7,8, and 9-tetrahydrochysene-5H-ring also [b] pyridine-9-alcohol adding in THF (400mL) in the 1L round-bottomed flask in heptan (6R, 9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine (19.58g also, 45.4mmol), obtain brown solution.Via syringe add TBAF (54.4mL, 54.4mmol) and with mixture in stirred overnight at room temperature.15h:LCMS shows conversion fully.Remove THF.Residue and 78213-100 are merged and between 400ml EtOAc and 300ml water, distribute.Separate each layer.Water layer extracts with EtOAc (50ml).The organic layer salt water washing that merges, dry and concentrated, obtain tawny oily matter.By the FCC careful purifying of 20%EtOAc/ hexane, this can remove depolarization speckle slightly.All products MeOH recrystallization.Obtain x-ray structure.Total recovery with respect to the hydroxyketone of protecting through TIPS surpasses 26%.All analytical data are with previous described consistent.MS (ESI) [M+H +]=276.15; 1HNMR (500MHz, δ ppm 8.45 (d, J=4.88Hz, 1H) 7.50 (d of chloroform-d), J=7.63Hz, 1H) 7.20 (dd, J=7.48,5.04Hz, 1H) 7.01-7.11 (m, 3H) 4.92 (dd, J=11.29,2.14Hz, 1H) 3.18-3.30 (m, 1H) 2.90-2.99 (m, 1H) 2.84 (d, J=14.04Hz, 1H) 2.33-2.43 (m, 1H) 2.16-2.26 (m, 2H) 1.56-1.73 (m, 1H).
Intermediate 52
Figure BPA00001276869200561
6-(2, the 3-difluorophenyl)-7,8-dihydro-5H-ring heptan is [b] pyridine-9 (6H)-ketone also
Under-55 ℃ and nitrogen in the 100mL round-bottomed flask of oven dry to CH 2Cl 2(0.131mL 1.497mmol), obtains colourless solution to add oxalyl chloride (4mL).Last 10 minutes and dropwise add DMSO (0.212mL, 2.99mmol).With the solution restir after 30 minutes, last 5 minutes via conduit add (6R, 9R)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol (206mg, 0.748mmol) (racemic) (with the dry-out benzene azeotropic) is at 2ml CH 2Cl 2In solution (and use 2ml drip washing).With reaction mixture at-50～-55 ℃ of restir 40 minutes (solution becomes emulsus).Add Et at-50 ℃ via syringe 3(0.521mL 3.74mmol) and with reaction mixture stirred 30 minutes N.Add entry and EtOAc, and separate each layer.Water layer extracts with EtOAc.The organic layer Na that merges 2SO 4Dry and concentrated, obtain tawny oily matter.TLC (1/1EtOAc/ hexane) demonstrates two spots: polarity is main spot and a spot of starting raw material spot of big (comparing with cis-alcohol).By FCC 60%EtOAc/ hexane purifying, a small amount of starting raw material that obtains required product [it is colorless oil (148mg, 72%)] and reclaim.MS(ESI)[M+H +]＝274.30。 1H NMR (400MHz, δ ppm8.57 (dd, J=4.66, the 1.64Hz of chloroform-d), 1H) 7.39 (d, J=7.81Hz, 1H) 7.20-7.31 (m, 1H) 6.83-7.04 (m, 2H) 6.72 (t, J=6.92Hz, 1H) 3.50 (dd, J=9.32,6.30Hz, 1H) 3.09 (d, J=6.30Hz, 2H) 2.84-2.99 (m, 1H) 2.68-2.84 (m, 1H) 2.03-2.17 (m, 1H) 1.85-2.02 (m, 1H); 13C NMR (100MHz, the δ ppm 203.43,154.56 of chloroform-d), 152.00-149.39 (dd, J=13.4 and 247Hz), 149.52-146.94 (dd, J=12.5 and 247Hz), 148.83,138.77,134.44,134.22 (d, J=11.0Hz), 125.87,124.16,122.36,115.40 (d, J=17.0Hz), 39.62,36.83,35.19,27.33.
Intermediate 53
Figure BPA00001276869200571
(E)-2-(6-(2, the 3-difluorophenyl)-7,8-dihydro-5H-ring heptan is [b] pyridine-9 (6H)-subunit also) ethyl acetate
Referring to Nagarajan, S.R.et al.Bioorg.Med.Chem.2007,15,3390-3412.In the 100mL round-bottomed flask, in toluene (6mL), add 6-(2, the 3-difluorophenyl)-7,8-dihydro-5H-ring heptan also [b] pyridine-9 (6H)-ketone (148mg, 0.542mmol) (with the dry-out benzene azeotropic) obtains colourless solution.Add (triphenyl phosphoranediyl) ethyl acetate (208mg, 0.596mmol), and with mixture heating up spend the night (4:30pm) that reflux.The 16h:LCMS demonstration is converted into required product fully.TLC (1/1EtOAc/ hexane) demonstrates a main spot (polarity is little compared with the trans alcohol of beginning raw material) that polarity is less.Remove toluene and residue by FCC 50%EtOAc/ hexane purifying, obtain required product, it is colorless oil (139mg, 75%).Carry out 1H NMR and 13C NMR also confirms that structure is an individual isomer.MS (ESI) [M+H +]=346.46; 1H NMR (400MHz, δ ppm 8.43 (dd, the J=4.78 of chloroform-d), 1.76Hz, 1H) 7.33 (dd, J=7.55,1.51Hz, 1H) 7.13 (dd, J=7.55,4.78Hz, 1H) 6.91-7.00 (m, 2H) 6.80-6.90 (m, 1H) 6.36 (s, 1H) 4.17 (q, J=7.05Hz, 2H) 3.25-3.43 (m, 2H) 3.04-3.14 (m, 1H) 2.93-3.05 (m, 1H) 2.88 (dd, J=14.86,3.27Hz, 1H) 2.04-2.21 (m, 1H) 1.83-2.02 (m, 1H) 1.25 (t, J=7.05Hz, 3H); 13CNMR (100MHz, the δ ppm 166.45,159.22,158.59 of chloroform-d), 151.99-149.47 (dd, J=13.4 and 247Hz), 149.39-146.90 (dd, J=12.7 and 245Hz), 147.55,137.88,135.46 (d, J=11.4Hz), 133.41,123.98,123.25,122.43,120.89,115.09 (d, J=16.9Hz), 59.94,38.62,36.30,32.49,28.85,14.27.
Intermediate 54
(E)-2-(6-(2, the 3-difluorophenyl)-7,8-dihydro-5H-ring heptan is [b] pyridine-9 (6H)-subunit also) acetate
(11.8mg 0.034mmol), obtains colourless solution to ethyl acetate to add (E)-2-(6-(2, the 3-difluorophenyl)-7,8-dihydro-5H-ring heptan is [b] pyridine-9 (6H)-subunit also) in the 50mL round-bottomed flask in THF (1ml).Add LiOH (0.2ml, 0.200mmol) and with mixture at stirred overnight at room temperature (4:30pm).16h:LCMS shows that a small amount of starting raw material is residual.Add 0.5ml MeOH and with mixture restir 24 hours.LCMS shows conversion fully.Concentrated and further dry with except that anhydrating under high vacuum, obtain white solid.Its following further drying: with dry-out benzene azeotropic and under high vacuum dry 4 hours.White solid is directly used in following reaction then.MS(ESI)[M+H +]＝316.21。
Intermediate 55
Figure BPA00001276869200582
(E)-1-(1-(2-(6-(2, the 3-difluorophenyl)-7,8-dihydro-5H-ring heptan is [b] pyridine-9 (6H)-subunit also) ethanoyl) piperidin-4-yl)-1H-imidazo [4,5-b] pyridines-2 (3H)-ketone
In the 100mL round-bottomed flask to CH 2Cl 2(6-(2 to add (E)-2-(2ml), the 3-difluorophenyl)-7,8-dihydro-5H-ring heptan is [b] pyridine-9 (6H)-subunit also) acetate (10.72mg, 0.034mmol) and 1-(piperidin-4-yl)-1H-imidazo [4,5-b] pyridine-2 (3H)-ketone (22.26mg, 0.102mmol) (dihydrochloride), obtain colourless suspension.Add to be permitted the uncommon alkali of Buddhist nun (0.030ml, 0.170mmol) and 3-(diethoxy phosphoryl oxygen base)-1,2,3-phentriazine-4 (3H)-ketone (20.35mg, 0.068mmol).Reaction mixture dilutes with DMF (0.5ml).Most of solid dissolving.With it stirring at room 44 hours.It dilutes with EtOAc and washes with water.Na is used in organic layer salt water washing 2SO 4Dry and concentrated, obtain tawny oily matter/gel.By FCC 8%MeOH/CH 2Cl 2Purifying obtains required product, and it is white foam shape thing (18mg, 100%).MS (ESI) [M+H +]=516.27; 1H NMR (400MHz, and the δ ppm11.18 of chloroform-d) (wide unimodal, 1H) 8.45 (dd, J=4.78,1.26Hz, 1H) 8.04 (d, J=5.04Hz, 1H) 7.39 (d, J=6.55Hz, 1H) 7.23-7.30 (m, 1H) 7.15 (dd, J=7.68,4.91Hz, 1H) 6.84-7.08 (m, 4H) 6.73 (d, J=2.52Hz, 1H) 4.91 (d, J=12.59Hz, 1H) 4.61 (td, J=12.15,3.65Hz, 1H) 4.34 (1H) 3.37 is (wide unimodal for d, J=12.84Hz, 1H) 3.02-3.31 (m, 3H) 2.66-2.97 (m, 3H) 2.05-2.36 (m, 4H) 1.86-2.00 (m, 2H).
Intermediate 56 and 57
Figure BPA00001276869200591
2-((6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) ethyl acetate and 2-((6, the 9-cis)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) ethyl acetate
(113.6mg 0.331mmol), obtains colourless solution to ethyl acetate to add (E)-2-(6-(2, the 3-difluorophenyl)-7,8-dihydro-5H-ring heptan is [b] pyridine-9 (6H)-subunit also) in the 50mL round-bottomed flask in MeOH (6mL).Adding Pd/C (35.2mg, 0.033mmol).Mixture was stirred 4 hours under the hydrogen air bag.With its filtration, washing also concentrates.Carry out FCC with the 50%EtOAc/ hexane, obtain two kinds of required products, it is colorless oil.Obtain 1 (50.0mg, 40.5%) and 2 (66.7mg, 54%) 1H NMR and 13C NMR also confirms said structure.Compare with the similar thing of carbamate, less a kind of product (1) most probable of polarity is trans-isomer(ide) (ratio of trans/cis is 1/1.33).MS (ESI) [M+H +]=346.25 (t R=2.20 and 2.42 minutes, on XBridge 4.6 * 50mm S5 chromatographic column, carried out 4 minutes).Trans product: 1H NMR (400MHz, δ ppm 8.32 (dd, the J=4.78 of chloroform-d), 1.51Hz, 1H) 7.36 (dd, J=7.43,1.64Hz, 1H) 6.93-7.09 (m, 4H) 4.06-4.23 (m, 2H) 3.68 (ddd, J=10.20,7.68,7.55Hz, 1H) 3.32-3.47 (m, 1H) 3.22 (dd, J=16.24,7.93Hz, 1H) 2.85-3.00 (m, 1H) 2.74 (d, J=14.10Hz, 1H) 2.59 (dd, J=16.12,7.05Hz, 1H) 2.04-2.17 (m, 2H) 1.91 (dt, J=13.85,3.40Hz, 1H) 1.43-1.61 (m, 1H) 1.17-1.28 (m, 3H); 13C NMR (100MHz, the δ ppm 173.58,162.50 of chloroform-d), 152.01-149.41 (dd, J=13.3 and 246Hz), 149.41-146.73 (dd, J=24.0 and 244Hz), 146.28,136.95,136.86,135.45,124.15,122.10,121.41,114.88 (d, J=17.0Hz), 60.13,41.59,40.78,38.58,38.38,37.76,32.90,14.27.Cis-product: 1H NMR (400MHz, δ ppm8.35 (dd, the J=4.91 of chloroform-d), 1.64Hz, 1H) 7.29 (dd, J=7.30,1.51Hz, 1H) 7.02 (dd, J=7.55,4.78Hz, 1H) 6.89-6.97 (m, 2H) 6.79-6.89 (m, 1H) 4.03-4.16 (m, 2H) 3.77 (dt, J=7.62,3.87Hz, 1H) 3.26 (wide unimodal, 1H) 3.10 (d, J=6.04Hz, 2H) 2.99 (dd, J=15.23,7.43Hz, 1H) 2.76 (dd, J=15.23,8.18Hz, 1H) 1.77-2.07 (m, 4H) 1.14-1.25 (m, 3H); 13CNMR (100MHz, the δ ppm 172.62,161.47 of chloroform-d), 152.00-149.40 (dd, J=13.7 and 247Hz), (149.53-146.75 dd, J=20.2 and 245Hz), 146.90,137.97,136.72 (d, J=11.4Hz), 133.82,123.96,122.41,121.71,114.82 (d, J=17.1Hz), 60.34,39.41,36.84,36.70,35.68,31.42,29.64,14.21.
Intermediate 58
Figure BPA00001276869200601
2-((6, the 9-cis)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) acetate
(66.7mg 0.193mmol), obtains colourless solution to ethyl acetate to add 2-((6, the 9-cis)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) in the 50mL round-bottomed flask in THF (2ml).Add LiOH (0.4ml, 0.400mmol) and with mixture in stirred overnight at room temperature.16h:LCMS shows that conversion is good with respect to starting raw material.Add 1ml MeOH and with mixture restir 24 hours.LCMS shows conversion fully.Concentrated and further dry with except that anhydrating under high vacuum, obtain white solid.Its following further drying: with dry-out benzene azeotropic and under high vacuum dry 4 hours.White solid is directly used in following reaction then.MS(ESI)[M+H +]＝318.22。
Embodiment 5
Figure BPA00001276869200602
1-(1-(2-((6, the 9-cis)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) ethanoyl) piperidin-4-yl)-1H-imidazo [4,5-b] pyridines-2 (3H)-ketone
In the 100mL round-bottomed flask to CH 2Cl 2Add 2-((6 (4ml), the 9-cis)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) acetate (61.2mg, 0.193mmol) and 1-(piperidin-4-yl)-1H-imidazo [4,5-b] (126mg, 0.579mmol) (dihydrochloride) obtains colourless suspension to pyridine-2 (3H)-ketone.Add to be permitted the uncommon alkali of Buddhist nun (0.169ml, 0.965mmol) and 3-(diethoxy phosphoryl oxygen base)-1,2,3-phentriazine-4 (3H)-ketone (115mg, 0.386mmol).Reaction mixture dilutes with DMF (1ml).Most of solid dissolving.With it in stirred overnight at room temperature.20h:LCMS shows no starting raw material, and demonstrates product and the less peak of polarity.44h: the less peak of polarity reduces.It dilutes with EtOAc and washes with water.Separate each layer.Na is used in organic layer salt water washing 2SO 4Dry and concentrated, obtain tawny oily matter.Use 8%MeOH/CH by FCC (ISCO) 2Cl 2Purifying obtains required product, and it is tawny foam (91mg, 87% (2 step)).LCMS：＞95％。 1H NMR confirms said structure.MS (ESI) [M+H +]=518.34; 1H NMR (400MHz, the δ ppm11.57 of chloroform-d) (wide unimodal, and 1H) 8.36 (wide unimodal, 1H) 8.04 (d, J=4.78Hz, 1H) 7.26-7.39 (m, 1H) 7.17-7.27 (m, 1H) 6.69-7.07 (m, 5H) 4.81 (t, J=15.36Hz, 1H) 4.61 (td, J=12.21,4.03Hz, 1H) 4.16-4.39 (m, 1H) 3.77-4.00 (m, 1H) 3.07-3.49 (m, 4H) 2.53-3.04 (m, 3H) 1.65-2.47 (m, 8H).
Intermediate 59
Figure BPA00001276869200611
2-((6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) acetate
(50.0mg 0.145mmol), obtains colourless solution to ethyl acetate to add 2-((6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) in the 50mL round-bottomed flask in THF (2ml).Add LiOH (0.4ml, 0.400mmol) and with mixture in stirred overnight at room temperature.16h:LCMS shows that a small amount of starting raw material is residual.Add 1ml MeOH and with mixture restir 24 hours.LCMS shows conversion fully.Mixture is concentrated and further dry with except that anhydrating under high vacuum, obtain white solid.Its following further drying: with dry-out benzene azeotropic and under high vacuum dry 4 hours.White solid is directly used in following reaction then.MS(ESI)[M+H +]＝318.22。
Embodiment 6 and 7
Figure BPA00001276869200621
1-(1-(2-((6R, 9S)-6-(2, the 3-difluorophenyl)-6; 7; 8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) ethanoyl) piperidin-4-yl)-1H-imidazo [4,5-b] pyridines-2 (3H)-ketone and 1-(1-(2-((6S; 9R)-6-(2; the 3-difluorophenyl)-6,7,8; 9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) ethanoyl) piperidin-4-yl)-1H-imidazo [4,5-b] pyridines-2 (3H)-ketone
In the 100mL round-bottomed flask to CH 2Cl 2Add 2-((6 (4ml), 9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) acetate (46.0mg, 0.145mmol) and 1-(piperidin-4-yl)-1H-imidazo [4,5-b] (95mg, 0.435mmol) (dihydrochloride) obtains colourless suspension to pyridine-2 (3H)-ketone.Add to be permitted the uncommon alkali of Buddhist nun (0.127ml, 0.725mmol) and 3-(diethoxy phosphoryl oxygen base)-1,2,3-phentriazine-4 (3H)-ketone (87mg, 0.290mmol).Reaction mixture dilutes with DMF (1ml).Most of solid dissolving.With it in stirred overnight at room temperature.44h:LCMS shows conversion fully.It dilutes with EtOAc and washes with water.Separate each layer.Na is used in organic layer salt water washing 2SO 4Dry and concentrated, obtain tawny oily matter/gel.Use 8%MeOH/CH by FCC (ISCO) 2Cl 2Purifying obtains required product, and it is tawny foam (68mg, 86% (2 step)).MS (ESI) [M+H +]=518.27; 1H NMR (400MHz, and the δ ppm 11.44 of chloroform-d) (wide unimodal, 1H) 8.25-8.42 (m, 1H) 8.05 (d, J=5.29Hz, 1H) 7.38 (t, J=8.44Hz, 1H) 7.20-7.31 (m, 1H) 6.83-7.10 (m, 5H) 4.87 (d, J=12.34Hz, 1H) 4.53-4.73 (m, 1H) 4.43 (t, J=15.36Hz, 1H) 3.81-4.00 (m, 1H) 3.36-3.60 (m, 2H) 3.24 (t, J=12.97Hz, 1H) 2.94 (t, J=11.21Hz, 1H) 2.33-2.80 (m, 4H) 2.05-2.31 (m, 3H) 1.80-2.05 (m, 3H) 1.38-1.63 (m, 1H).Racemic product is by chirality HPLC (the analytical chromatographic column 4.6 * 250mm of Chiralpak AD-H, 5 μ m; Moving phase: 40%MeOH/CO 2Column temperature: 35 ℃; Flow velocity: 2.0mL/min (lasting 26 minutes); Injection volume: 5 μ L concentration are the MeOH solution of about 2mg/mL) split.(6R 9S) is t to compound RFirst peak of=13.88 minutes, and compound (6S 9R) is t RSecond peak of=19.19 minutes.
Intermediate 60
Figure BPA00001276869200631
Trans-2-(6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) isoindoline-1, the 3-diketone
In the 500mL round-bottomed flask to CH 2Cl 2Add (6, the 9-cis)-6-(2, the 3-difluorophenyl)-6,7,8 (40mL), 9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol (1.56g, 5.67mmol) (with the dry-out benzene azeotropic) obtains colourless solution.Add isoindoline-1 at 0 ℃, the 3-diketone (1.667g, 11.33mmol) and triphenylphosphine (2.97g, 11.33mmol), then add DIAD (1.653mL, 8.50mmol).Mixture is warmed to ambient temperature overnight under nitrogen.17h:LCMS shows conversion fully.It is concentrated into dried.Directly carry out FCC, obtain two approaching peaks with the 50%EtOAc/ hexane.With blended peak (by product that comprises dehydration) merging and concentrated, obtain white solid, it is directly used in following steps.MS(ESI)[M+H +]＝405.23。
Intermediate 61
Figure BPA00001276869200632
Trans-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-amine also
Add 2-((6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) isoindoline-1 in the 500mL round-bottomed flask in MeOH (50mL), (2.293g 5.67mmol), obtains white suspension to the 3-diketone.(5mL 159mmol) (uses the 5ml hydrazine hydrate), and in the oil bath of preheating mixture is stirred 5 hours (solid fades away and new solid is separated out gradually) under 70 ℃ and nitrogen to add hydrazine.LCMS shows conversion fully.Residue is distributed between 0.5N NaOH and EtOAc.Separate each layer and water layer extracts with EtOAc.The organic layer salt water washing that merges, dry and concentrated.With 10%MeOH (containing 2M ammonia)/CH 2Cl 2Carry out FCC, obtain required product, it is colorless oil (0.65g, 42% (2 step) (some may lose during purifying)), and described oily matter is white solid leaving standstill after fixing.MS (ESI) [M+H +]=275.26; 1H NMR (400MHz, δ ppm 8.38 (d, J=4.78Hz, 1H) 7.30-7.41 (m of chloroform-d), 1H) 6.89-7.10 (m, 4H) 4.28 (d, J=10.58Hz, 1H) 3.13-3.29 (m, 1H) 2.63-3.00 (m, 4H) 2.02-2.15 (m, 3H) 1.51-1.70 (m, 1H); 13CNMR (100MHz, the δ ppm 170.83 of chloroform-d), 151.85-149.39 (dd, J=13.3 and 246Hz), (149.29-146.72 d, J=12.5 and 245Hz), 146.24,137.11,136.62 (d, J=11.6Hz), 134.30,124.17,122.10,121.78,114.95 (d, J=17.1Hz), 55.25,40.52,37.57,37.04,37.00.
Intermediate 62
Figure BPA00001276869200641
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid benzene methyl
The oven dry the 500mL round-bottomed flask in to CH 2Cl 2(2.91g 9.99mmol), obtains the tawny suspension to add 1-(piperidin-4-yl)-1H-imidazo [4,5-b] pyridines-2 (3H)-ketone dihydrochloride (50mL).Under nitrogen, add Et 3N (5.57mL, 40.0mmol).Via syringe dropwise add the chloroformic acid benzene methyl (1.421mL, 9.99mmol).With mixture at stirred overnight at room temperature (2:00pm).LCMS shows good conversion (some starting raw materials are residual).Reaction mixture dilutes with EtOAc and water.Separate each layer.Organic layer salt water washing, dry and concentrated.Residue is by FCC 8%MeOH/CH 2Cl 2Purifying obtains required product, and it is colorless oil (2.17g, 62%).MS(ESI)[M+H +]＝353.30。It need not further sign and promptly is used for following steps.
Intermediate 63
Figure BPA00001276869200642
4-(2-oxo-3-((2-(trimethyl silyl) oxyethyl group) methyl)-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid benzene methyl
(1.62g 4.60mmol), obtains colourless solution to piperidines-1-carboxylic acid benzene methyl to add 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) in the 500mL round-bottomed flask in THF (40mL).Add NaH (0.552g, 22.99mmol) (excessive).Under nitrogen, stir after 5 minutes, and adding SEM-Cl (0.897mL, 5.06mmol).With mixture in stirred overnight at room temperature.16h:LCMS shows good conversion.Reaction mixture (is emitted gas with EtOAc dilution and the slow cancellation of water! ).Separate each layer.Organic layer salt water washing, dry and concentrated, obtain little green oily matter.
TLC (10%MeOH/CH 2Cl 2) demonstrate blue main spot (Rf is about 0.25) (polarity is slightly little compared with the beginning raw material).By FCC 10%MeOH/CH 2Cl 2Purifying obtains required product, and it is colorless oil (1.92g, 87%).MS (ESI) [M+H +]=483.33; 1H NMR (400MHz, δ ppm7.25-7.40 (m, 6H) 6.82-6.94 (m, 1H) 6.60 (t of chloroform-d), J=7.05Hz, 1H) 5.66 (s, 2H) 5.11 (s, 2H) 4.45-4.63 (m, 1H) 4.33 (wide unimodal, 2H) 3.55-3.69 (m, 2H) 2.88 (d, J=1.01Hz, 2H) 2.06 (d, J=9.06Hz, 2H) 1.80 (d, J=11.58Hz, 2H) 0.82-1.00 (m, 2H)-0.13 to-0.03 (m, 9H).
Intermediate 64
1-(piperidin-4-yl)-3-((2-(trimethyl silyl) oxyethyl group) methyl)-1H-imidazo [4,5-b] pyridines-2 (3H)-ketone
In the 500mL round-bottomed flask, in MeOH (30mL), add 4-(2-oxo-3-((2-(trimethyl silyl) oxyethyl group) methyl)-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) (1.85g 3.83mmol), obtains colourless solution to piperidines-1-carboxylic acid benzene methyl.(0.408g 0.383mmol), and stirs mixture and to spend the night under the hydrogen air bag to add Pd/C.17h:LCMS shows conversion fully.With its filtration, washing also concentrates under high vacuum, obtains colourless foam shape thing (1.31g, 100%).MS (ESI) [M+H +]=349.29; 1H NMR (400MHz, δ ppm 9.55 (broad peak, 1H) 7.64-8.06 (m of chloroform-d), 1H) 7.42 (wide unimodal, 1H) 6.81 (wide unimodal, 1H) 5.66 is (wide unimodal, 2H) 4.73 (d, J=13.85Hz, 1H) 3.42-3.89 (m, 4H) 3.08-3.42 (m, 2H) 2.88 (wide unimodal, 2H) 1.72-2.16 (m, 2H) 0.76-0.94 (m, 2H)-0.22 to-0.08 (m, 9H).
Intermediate 65
Figure BPA00001276869200652
N-((6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also)-4-(2-oxo-3-((2-(trimethyl silyl) oxyethyl group) methyl)-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide
The oven dry the 100mL round-bottomed flask in to CH 2Cl 2((2-(trimethyl silyl) oxyethyl group) methyl)-(262mg 0.752mmol), obtains colourless solution to 1H-imidazo [4,5-b] pyridines-2 (3H)-ketone to add 1-(piperidin-4-yl)-3-(8mL).Under nitrogen, add Et 3(0.192mL 1.379mmol) and with mixture is cooled to-20 ℃ to N.Dropwise add trichloro-methyl chloroformate (0.061mL, 0.502mmol).Mixture under agitation is warmed to 10 ℃ and kept 1 hour gradually, and solution becomes little yellow during this period.TLC (10%MeOH/CH 2Cl 2) demonstrate the main spot of the less sapphirine of polarity and do not have the starting raw material spot at baseline.It is being concentrated into dried (white solid) and further drying under high vacuum under vacuum.Add (6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8 in room temperature via conduit, 9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-amine (172mg, 0.627mmol) and Et 3N (0.192mL, 1.379mmol) solution in 1ml THF (and using 2ml drip washing).Add Et again 3N (0.192mL, 1.379mmol).Resulting light yellow suspension stirred under nitrogen spend the night.16h:LCMS shows conversion fully.Its water and EtOAc dilution.Separate each layer.Na is used in organic layer salt water washing 2SO 4Dry and concentrated.By FCC 10%MeOH/CH 2Cl 2Purifying obtains required product (465mg, 93%).MS (ESI) [M+H +]=649.34; 1H NMR (500MHz, δ ppm 8.36 (d, J=4.88Hz, 1H) 7.96-8.09 (m of chloroform-d), 1H) 7.55 (d, J=4.27Hz, 1H) 7.46 (d, J=7.63Hz, 1H) 7.29 (d, J=7.93Hz, 1H) 7.13 (t, J=6.10Hz, 1H) 6.97-7.09 (m, 3H) 6.93 (dd, J=7.32,5.49Hz, 1H) 5.39 (s, 2H) 5.11 (dd, J=10.38,3.66Hz, 1H) 4.53-4.66 (m, 1H) 4.33 (t, J=11.29Hz, 2H) 3.70 (t, J=8.24Hz, 2H) 3.25-3.44 (m, 1H) 2.84-3.05 (m, 3H) 2.77 (d, J=14.04Hz, 1H) 2.19-2.50 (m, 4H) 2.11 (d, J=14.04Hz, 1H) 1.91 (d, J=11.29Hz, 2H) 1.53 (t, J=12.05Hz, 1H) 0.95 (t, J=8.24Hz, and 2H)-0.06 (s, 9H).
Embodiment 8 and 9
Figure BPA00001276869200661
N-((6R, 9R)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also)-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide and N-((6S, 9S)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also)-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide
In the 250mL round-bottomed flask to CH 2Cl 2Add N-((6 (4mL), 9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also)-4-(2-oxo-3-((2-(trimethyl silyl) oxyethyl group) methyl)-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) (200mg 0.308mmol), obtains brown solution to piperidines-1-methane amide (racemic).Add TFA (1.000mL), and with mixture stirring at room 1 hour.LCMS shows conversion fully.Remove volatile matter.Residue is distributed between 0.5N NaOH and EtOAc.Separate each layer and water layer and extract (LCMS shows does not have product in water layer) with EtOAc.The organic layer salt water washing that merges, dry and concentrated, obtain the tawny foam.By FCC 10%MeOH/CH 2Cl 2Purifying obtains required racemic product (118mg, 74%), and it is colourless foam shape thing/solid.LCMS shows purity＞95%.MS(ESI)[M+H +]＝519.24。 1H NMR (400MHz, and the δ ppm 11.78 of chloroform-d) (wide unimodal, 1H) 8.23-8.41 (m, 1H) 7.98 (d, J=4.28Hz, 1H) 7.56 (d, J=4.28Hz, 1H) 7.34-7.47 (m, 1H) 7.19-7.33 (m, 1H) 7.07 (dd, J=7.43,4.91Hz, 1H) 6.90-7.02 (m, 3H) 6.87 (dd, J=7.81,5.29Hz, 1H) 5.12 (dd, J=10.45,3.90Hz, 1H) 4.46-4.64 (m, 1H) 4.19-4.42 (m, 2H) 3.28 (t, J=12.59Hz, 1H) 2.88-3.05 (m, 2H) 2.77-2.86 (m, 1H) 2.71 (d, J=13.85Hz, 1H) 2.41 (d, J=13.35Hz, 1H) 2.14-2.34 (m, 3H) 2.04 (d, J=12.09Hz, 1H) 1.86 (d, J=10.32Hz, 2H) 1.37-1.58 (m, 1H).Racemic product is by chirality HPLC (the analytical chromatographic column 4.6 * 250mm of Chiralpak AD-H, 5 μ m; Moving phase: 40%MeOH/CO 2Column temperature: 35 ℃; Flow velocity: 2.0mL/min (lasting 32 minutes); Carry out ultraviolet detection at 292nm; Injection volume: 5 μ L concentration are the MeOH solution of about 2mg/mL) split.(6R 9R) is t to compound RFirst peak of=15.26 minutes, and compound (6S 9S) is t RSecond peak of=24.98 minutes.
Intermediate 66
Figure BPA00001276869200671
(E)-and 6-phenyl-9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan is [b] pyridine also
Under nitrogen with phenyl-boron dihydroxide (0.060g, 0.495mmol), yellow soda ash (0.382mL, 0.764mmol), trifluoromethanesulfonic acid (E)-9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan is [b] pyridine-6-base ester (0.1922g also, 0.413mmol) and tetrakis triphenylphosphine palladium (0) (0.024g, 0.021mmol) mixture heating up to 80 in toluene (5mL) and MeOH (1mL) ℃ and keeping 3 hours.LCMS shows no starting raw material.Reaction mixture dilutes with ethyl acetate and washes with water once.The separating ethyl acetate layer, dry (Na 2SO 4), filter and concentrate, obtain crude product.Crude product in statu quo uses.MS(ESI)[M+H +]＝394.32。
Intermediate 67
(E)-and 6-(2, the 5-difluorophenyl)-9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan is [b] pyridine also
Under nitrogen with 2,5-difluorophenyl boric acid (0.088g, 0.554mmol), yellow soda ash (0.427mL, 0.854mmol), corresponding reactant and tetrakis triphenylphosphine palladium (0) (0.027g, 0.023mmol) mixture heating up to 80 in toluene (5mL) and MeOH (1mL) ℃ and keeping 3 hours.LCMS shows no starting raw material.Reaction mixture dilutes with ethyl acetate and washes with water once.The separating ethyl acetate layer, dry (Na 2SO 4), filter and concentrate, obtain crude product.Crude product in statu quo uses.MS(ESI)[M+H +]＝430.29。
Intermediate 68
Figure BPA00001276869200682
(E)-and 6-(3, the 4-difluorophenyl)-9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan is [b] pyridine also
Under nitrogen with 3,4-difluorophenyl boric acid (0.083g, 0.527mmol), yellow soda ash (0.406mL, 0.813mmol), trifluoromethanesulfonic acid (E)-9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan is [b] pyridine-6-base ester (0.2045g also, 0.439mmol) and tetrakis triphenylphosphine palladium (0) (0.025g, 0.022mmol) mixture heating up to 80 in toluene (5mL) and MeOH (1mL) ℃ and keeping 3 hours.LCMS shows no starting raw material.Reaction mixture dilutes with ethyl acetate and washes with water once.The separating ethyl acetate layer, dry (Na 2SO 4), filter and concentrate, obtain crude product.Crude product in statu quo uses.MS(ESI)[M+H +]＝430.36。
Intermediate 69
Figure BPA00001276869200691
(E)-and 6-phenyl-8,9-dihydro-7H-ring heptan is [b] pyridine-9-alcohol also
Room temperature with TBAF (1.041mL 1.041mmol) is added to (E)-6-phenyl-9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan also [b] pyridine (0.2049g is in THF 0.521mmol) (5mL) solution.With reaction mixture stirring at room 6 hours.Solvent removed in vacuo obtains crude product.MS(ESI)[M+H +]＝238.25。
Intermediate 70
Figure BPA00001276869200692
(E)-and 6-(2, the 5-difluorophenyl)-8,9-dihydro-7H-ring heptan is [b] pyridine-9-alcohol also
Room temperature with TBAF (0.954mL 0.954mmol) is added to (E)-6-(2, the 5-difluorophenyl)-9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan also [b] pyridine (0.2049g is in THF 0.477mmol) (5mL) solution.With reaction mixture stirring at room 6 hours.Solvent removed in vacuo and product come purifying (with 0% to 50% to 100% ethyl acetate/hexane wash-out) (102.2mg, 78%) by the flash chromatography post.MS(ESI)[M+H +]＝274.23。 1H NMR (400MHz, δ ppm 8.37 (dd, J=4.78, the 1.26Hz of chloroform-d), 1H) 7.51 (dd, J=7.81,1.26Hz, 1H) 7.17-7.27 (m, 1H) 6.87-7.05 (m, 3H) 6.44 (s, 1H) 5.74 (wide unimodal, 1H) 4.77 (dd, J=10.45,2.64Hz, 1H) 2.79-2.93 (m, 1H) 2.66-2.77 (m, 1H) 2.48-2.60 (m, J=13.53,5.45,5.45,2.77Hz, 1H) 1.97-2.11 (m, 1H).
Intermediate 71
Figure BPA00001276869200693
(E)-and 6-(3, the 4-difluorophenyl)-8,9-dihydro-7H-ring heptan is [b] pyridine-9-alcohol also
Room temperature with TBAF (0.878mL 0.878mmol) is added to (E)-6-(3, the 4-difluorophenyl)-9-(triisopropyl silyl oxygen base)-8,9-dihydro-7H-ring heptan also [b] pyridine (0.189g is in THF 0.439mmol) (5mL) solution.With reaction mixture stirring at room 6 hours.Solvent removed in vacuo and product come purifying (with 0% to 50% to 100% ethyl acetate/hexane wash-out) (93.5mg, 78%) by the flash chromatography post.MS(ESI)[M+H +]＝274.23。
General method of reducing: substrate (from the TBAF deprotection) and Pd/C (10% gac) (5%mol) solution in MeOH (5mL) spend the night with the hydrogenation of hydrogen air bag in room temperature.The reaction mixture filtration is washed by plug of celite and with ethyl acetate.Filtrate is concentrated and product comes purifying (with 0% to 50% to 100% ethyl acetate/hexane wash-out) by the flash chromatography post.Trans product (as secondary product) at first wash-out comes out, and cis-product (as primary product) is that polarity is bigger.
Intermediate 72
Figure BPA00001276869200701
(6,9-is trans)-6-phenyl-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
Obtain the 15mg product by the 0.224mmol starting raw material.With the merging yield of cis-isomeride be 98%.MS(ESI)[M+H +]＝240.32。
Intermediate 73
Figure BPA00001276869200702
(6, the 9-cis)-6-phenyl-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
Obtain the 38mg product by the 0.224mmol starting raw material.With the merging yield of trans-isomer(ide) be 98%.MS(ESI)[M+H +]＝240.32。
Intermediate 74
Figure BPA00001276869200711
(6,9-is trans)-6-(2, the 5-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
Obtain 19.3mg product (trans product, the spot that polarity is less, Rf are about 0.7 (25% ethyl acetate/hexane)) by the 0.374mmol starting raw material.With the merging yield of cis-isomeride be 90%. 1HNMR (400MHz, δ ppm 8.36-8.45 (m, 1H) 7.46 (dd, the J=7.55 of chloroform-d), 1.26Hz, 1H) 7.16 (dd, J=7.43,4.91Hz, 1H) 6.94-7.04 (m, 2H) 6.83-6.92 (m, 1H) 4.87 (dd, J=11.33,2.01Hz, 1H) 3.05-3.19 (m, 1H) 2.74-2.89 (m, 2H) 2.25-2.35 (m, 1H) 2.06-2.17 (m, 2H) 1.56-1.68 (m, 2H).
Intermediate 75
Figure BPA00001276869200712
(6, the 9-cis)-6-(2, the 5-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
Obtain 92.4mg product (Rf is about 0.5 (50% ethyl acetate/hexane) for cis-product, the peak that polarity is bigger) by the 0.374mmol starting raw material.With the merging yield of trans-isomer(ide) be 90%. 1HNMR (400MHz, δ ppm 8.18-8.33 (m, 1H) 7.22-7.35 (m, 1H) 7.03 (dd of chloroform-d), J=7.55,5.04Hz, 1H) 6.93 (td, J=9.25,4.66Hz, 1H) 6.70-6.87 (m, 2H) 4.92-5.07 (m, 1H) 3.34-3.45 (m, 1H) 3.29 (t, J=8.44Hz, 1H) 2.89 (dd, J=14.10,2.27Hz, 1H) 2.14-2.30 (m, 1H) 1.91-2.11 (m, 3H).
Intermediate 76
Figure BPA00001276869200713
(6,9-is trans)-6-(3, the 4-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
Obtain the 15mg product by the 0.342mmol starting raw material.With the merging yield of cis-isomeride be 86%.MS (ESI) [M+H +]=276.23; 1H NMR (400MHz, δ ppm 8.30-8.48 (m, 1H) 7.41-7.49 (m of chloroform-d), 1H) 6.88-7.18 (m, 4H) 5.93 (wide unimodal, 1H) 4.85 (dd, J=11.21,2.14Hz, 1H) 3.10 (dd, J=14.10,11.58Hz, 1H) 2.71-2.85 (m, 1H) 2.47-2.57 (m, 1H) 2.27-2.36 (m, 1H) 1.97-2.18 (m, 2H) 1.47-1.68 (m, 1H).
Intermediate 77
Figure BPA00001276869200721
(6, the 9-cis)-6-(3, the 4-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
Obtain the 66.4mg product by the 0.342mmol starting raw material.With the merging yield of trans-isomer(ide) be 86%.MS (ESI) [M+H +]=276.23; 1H NMR (400MHz, δ ppm 8.33 (dd, J=5.04, the 1.51Hz of chloroform-d), 1H) 7.23-7.31 (m, 1H) 7.07 (dd, J=7.43,4.91Hz, 1H) 6.93-6.99 (m, 1H) 6.80-6.85 (m, 1H) 6.75 (dd, J=4.15,2.14Hz, 1H) 5.27 (wide unimodal, 1H) 4.95 (dd, J=9.19,2.64Hz, 1H) 3.15-3.33 (m, 1H) 3.00-3.13 (m, 2H) 2.01-2.25 (m, 3H) 1.83-1.97 (m, 1H).
Embodiment 10
Figure BPA00001276869200722
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6,9-is trans)-6-phenyl-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also
In room temperature with NaH (0.025g, 1.003mmol) be added to 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid 4-nitrophenyl ester and triethylamine (1: 3) tri hydrochloride (and 0.080g, 0.100mmol) and (6R, 9R)-6-phenyl-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol (0.016g is in THF 0.067mmol) (5mL) suspension.With reaction mixture stirring at room 4 hours.Reaction mixture comes cancellation by adding entry.Reaction mixture is further distributed between ethyl acetate and water.The separating ethyl acetate layer washes twice with water, dry then (Na 2SO 4), filter and concentrate.Carry out the flash chromatography post (with 0% to 5% to 10% methyl alcohol/CH 2Cl 2Wash-out) (31.1mg, 87%).MS (ESI) [M+H +]=484.20; 1H NMR (500MHz, δ ppm 8.45 (d, the J=4.58Hz of chloroform-d), 1H) 8.08 (d, J=5.19Hz, 1H) 7.40 (d, J=7.32Hz, 2H) 7.33 (t, J=7.78Hz, 2H) 7.23 (3H) 7.12 is (wide unimodal for d, J=7.93Hz, 1H) 6.93-7.00 (m, 1H) 6.05 (d, J=10.99Hz, 1H) 4.64 (wide unimodal, 3H) 3.33 (dd, J=13.89,11.75Hz, 1H) 3.05 (wide unimodal, 2H) 2.88 (d, J=14.34Hz, 1H) 2.61 (td, J=11.06,3.20Hz, 1H) 1.79-2.35 (m, 9H).
Embodiment 11
Figure BPA00001276869200731
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6,9-is trans)-6-(2, the 5-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also
In room temperature with NaH (0.036g, 1.417mmol) be added to 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid 4-nitrophenyl ester and triethylamine (1: 3) tri hydrochloride (0.113g, 0.142mmol) and (6R, 9R)-6-(2, the 5-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol with (6S, 9S)-6-(2, the 5-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol (1: 1) (0.052g is in THF 0.094mmol) (5mL) suspension.With reaction mixture stirring at room 4 hours.Reaction mixture comes cancellation by adding entry.Reaction mixture is further distributed between ethyl acetate and water.The separating ethyl acetate layer also washes twice with water, dry then (Na 2SO 4), filter and concentrate.Carry out the flash chromatography post (with 0% to 5% to 10% methyl alcohol/CH 2Cl 2Wash-out), obtain required product (32.2mg, 63%).MS (ESI) [M+H +]=520.25; 1H NMR (400MHz, and the δ ppm 10.77 of chloroform-d) (wide unimodal, 1H) 8.45 (d, J=4.03Hz, 1H) 8.07 (d, J=4.78Hz, 1H) 7.42 (2H) 7.13 is (wide unimodal for d, J=6.80Hz, 1H) 6.93-7.05 (m, 3H) 6.84-6.92 (m, 1H) 6.02 (d, J=10.83Hz, 1H) 4.34-4.81 (m, 3H) 3.30 (t, J=12.59Hz, 1H) 2.87-3.19 (m, 3H) 2.81 (1H) 2.63 is (wide unimodal for d, J=14.35Hz, 1H) 2.23-2.39 (m, 2H) 2.12-2.22 (m, 2H) 1.90 (wide unimodal, 3H); 19FNMR (376MHz, and the δ ppm-118.29 of chloroform-d) (d, J=17.24Hz, 1F)-124.51 (d, J=17.24Hz, 1F).
Embodiment 12
Figure BPA00001276869200741
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6,9-is trans)-6-(3, the 4-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also
In room temperature with NaH (0.056g, 2.231mmol) be added to 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) (0.178g is 0.223mmol) and in THF (5mL) suspension of corresponding reactant for piperidines-1-carboxylic acid 4-nitrophenyl ester and triethylamine (1:3) tri hydrochloride.With reaction mixture stirring at room 4 hours.Reaction mixture comes cancellation by adding entry.Reaction mixture is further distributed between ethyl acetate and water.The separating ethyl acetate layer washes twice with water, dry then (Na 2SO 4), filter and concentrate.Carry out the flash chromatography post (with 0% to 5% to 10% methyl alcohol/CH 2Cl 2Wash-out), obtain required product (33.7mg, 41.9%).MS (ESI) [M+H +]=520.27; 1H NMR (400MHz, and the δ ppm 10.75 of chloroform-d) (wide unimodal, 1H) 8.45 (d, J=3.78Hz, 1H) 8.07 (d, J=5.04Hz, 1H) 7.40 (d, J=7.05Hz, 2H) 6.86-7.16 (m, 5H) 6.00 (d, J=10.83Hz, 1H) 4.33-4.76 (m, 3H) 3.26 (dd, J=13.85,11.58Hz, 1H) 3.03 (wide unimodal, 2H) 2.80 (s, 1H) 2.50-2.66 (m, 1H) 1.82-2.21 (m, 6H) 1.19-1.28 (m, 2H); 19F NMR (376MHz, the δ ppm-138.37 of chloroform-d) to-135.13 (m, 1F)-141.92-139.34 (m, 1F).
Intermediate 78
Figure BPA00001276869200742
2 '-oxo-1 ', 2 '-dihydro spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-1-carboxylic acid 4-nitrophenyl ester
In the 50mL round-bottomed flask to CH 2Cl 2[piperidines-4, (187mg, 0.853mmol) (174mg 0.861mmol), obtains brown solution to 4 '-pyrido [2,3-d] [1,3] oxazine]-2 ' (1 ' H)-ketone for (with the dry-out benzene azeotropic) and chloroformic acid 4-nitrophenyl ester to add spiral shell (6mL).Add Et 3(0.238mL 1.706mmol), stirs spend the night (4:00pm) with mixture to N under room temperature and nitrogen, spend weekend then.Mixture still contains some solids.Add 5ml CHCl 3With dissolved solids and with clear yellow solution restir one day.TLC shows no starting raw material amine.It is further dry under high vacuum that it is concentrated into dry doubling.Residue in statu quo uses then.
Embodiment 13
Figure BPA00001276869200751
2-oxo-1, [benzo [d] [1,3] oxazine-4,4 '-piperidines]-1 '-carboxylic acid (6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also for 2-dihydro spiral shell
In the 100mL round-bottomed flask, in THF (5mL), add (6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol (79.3mg, 0.288mmol) (with the dry-out benzene azeotropic) and 2 '-oxo-1 ' also, 2 '-dihydro spiral shell [piperidines-4,4 '-pyrido [2,3-d] [1,3] oxazine]-1-carboxylic acid 4-nitrophenyl ester (221mg, 0.576mmol), obtain the tawny suspension.Under nitrogen, add NaH (69.1mg, 2.88mmol) (excessive).Mixture stirred under room temperature and nitrogen spend the night.17h:LCMS demonstrates two small peaks, and one of them may be product.Its water cancellation (is emitted gas! ) and extract with EtOAc.Separate each layer and water layer extracts with EtOAc.Na is used in the organic layer salt water washing that merges 2SO 4Dry and concentrated.By FCC 8%MeOH/CH 2Cl 2Purifying obtains required product, and it is colorless solid (10.8mg, 7.2%).MS (ESI) [M+H +]=521.39; 1H NMR (400MHz, and the δ ppm9.88 of chloroform-d) (wide unimodal, 1H) 8.23-8.53 (m, 2H) 7.50 (wide unimodal, 1H) 7.36-7.45 (m, 1H) 6.91-7.18 (m, 5H) 5.99 (1H) 4.39 is (wide unimodal for d, J=10.32Hz, 2H) 3.22-3.71 (m, 3H) 2.90-3.05 (m, 1H) 2.81 (d, J=14.35Hz, 1H) 1.85-2.55 (m, 6H) 1.67 (s, 2H).
Intermediate 79
Figure BPA00001276869200752
(6R, 9R)-6-(2, the 3-difluorophenyl)-3-nitro-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol in the 500mL round-bottomed flask to CH 2Cl 2Add (80mL) (6R, 9R)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol (2.912g also, 10.58mmol) (6.44g 21.16mmol), obtains colourless solution for (chirality) (with the dry-out benzene azeotropic) and tetrabutyl ammonium nitrate.Under nitrogen, dropwise add TFAA (3.29mL, 23.27mmol) (3:00pm) via syringe.With mixture at stirred overnight at room temperature (4:00pm).17h: remove volatile matter and residue is dissolved among the 60ml THF.Adding 15ml water and lithium hydroxide (1.267g, 52.9mmol).With mixture stirring at room 2 hours.LCMS shows CF 3The CO-product is hydrolyzed.It dilutes with EtOAc.Separate each layer.Organic layer salt water washing, dry and concentrated, obtain tawny oily matter.By FCC with 50%EtOAc/ hexane purifying, obtain the less peak of polarity (by 1H NMR determines to be nitric ether), starting raw material (0.54g, 18.5%) and product (376mg, 11%).MS (ESI) [M+H +]=321.11; 1H NMR (400MHz, δ ppm9.29 (d, the J=2.27Hz of chloroform-d), 1H) 8.32 (d, J=2.27Hz, 1H) 7.00-7.18 (m, 3H) 5.48 (d, J=3.02Hz, 1H) 5.06 (d, J=11.58Hz, 1H) 3.28-3.44 (m, 1H) 2.88-3.08 (m, 2H) 2.36-2.48 (m, 1H) 2.16-2.34 (m, 2H) 1.66-1.74 (m, 1H).
Intermediate 80
N-((6R, 9R)-6-(2, the 3-difluorophenyl)-3-nitro-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also)-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide
In the 100mL round-bottomed flask, in THF (4mL), add (6R, 9R)-6-(2, the 3-difluorophenyl)-and 3-nitro-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol (76.3mg also, 0.238mmol) (with the dry-out benzene azeotropic) and 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid 4-nitrophenyl ester (285mg, 0.357mmol), obtain yellow suspension.Under room temperature and nitrogen, add NaH (57.2mg, 2.382mmol) (excessive).Mixture was stirred 4 hours under room temperature and nitrogen.The slow cancellation of reaction mixture water also extracts with EtOAc.Separate each layer.Organic layer salt water washing, dry and concentrated.Dark oily matter is by FCC 10%MeOH/CH 2Cl 2Purifying.Required product (it is a main peak) is concentrated, obtain greenish orange look solid (17.1mg, 13%).MS(ESI)[M+H +]＝565.03。
Embodiment 14
Figure BPA00001276869200771
N-((6R, 9R)-3-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also)-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide
In the 100mL round-bottomed flask, in MeOH (2mL), add 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6R, 9R)-6-(2, the 3-difluorophenyl)-3-nitro-6,7,8,9-tetrahydrochysene-5H-encircles heptan, and also [b] pyridine-(17.1mg 0.030mmol), obtains the tawny suspension to 9-base ester.Adding Pd/C (17mg, 0.016mmol), and with mixture 4 hours (10:30am) of stirring under hydrogen (air bag).LCMS shows conversion fully.With its filtration and concentrated.Residue is by FCC 10%MeOH/CH 2Cl 2Purifying obtains required product, and it is white solid (7.0mg, 39%).MS (ESI) [M+H +]=535.05; 1H NMR (400MHz, the δ ppm 10.05 of chloroform-d) (wide unimodal, 1H) 8.05-8.15 (m, 1H) 8.00 is (wide unimodal, 1H) 7.36-7.59 (m, 1H) 7.28 (s, 1H) 6.91-7.13 (m, 4H) 5.97 (d, J=10.32Hz, 1H) 4.28-4.80 (m, 3H) 3.54-4.04 (m, 1H) 3.16-3.36 (m, 1H) 3.04 is (wide unimodal, 3H) 2.76 (d, J=14.35Hz, 1H) 2.23-2.44 (m, 2H) 2.05-2.23 (m, 3H) 1.77-2.05 (m, 4H).
Intermediate 81
Figure BPA00001276869200772
(6R, 9R)-3-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
With Pd/C (37mg, 0.035mmol) and (6R, 9R)-6-(2, the 3-difluorophenyl)-and 3-nitro-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol (300mg, 0.937mmol) mixture in methyl alcohol (10mL) is in hydrogen (air bag) hydrogenation 4 hours down.LCMS demonstration reaction is finished.Plug of celite is passed through in the reaction mixture filtration.Filtrate is concentrated, obtain crude product.MS (ESI) [M+H +]=291.29; 1HNMR (400MHz, (wide unimodal, 1H) 7.02 is (wide unimodal for the δ ppm 7.84 of chloroform-d), 3H) 6.79 (wide unimodal, and 1H) 5.90 (wide unimodal, 1H) 4.74 (d, J=10.32Hz, and 1H) 3.87 (wide unimodal, 2H) 3.06 (t, J=12.34Hz, and 1H) 2.86 (wide unimodal, 1H) 2.62 (d, J=13.85Hz, 1H) 2.26 (d, J=12.34Hz, 1H) 1.96-2.12 (m, 3H) 1.52 (wide unimodal, 1H).
Intermediate 82
(6R, 9R)-6-(2, the 3-difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
Room temperature with sodium cyanoborohydride (242mg, 3.86mmol) be added to (6R, 9R)-3-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol (56mg, 0.193mmol) and formaldehyde (1mL is in acetonitrile 13.43mmol) (2mL) solution.With reaction mixture stirring at room 4 hours.(0.5mL 8.73mmol) is added in the reaction mixture (noting: observe the heat release that causes that acetonitrile refluxes) and reaction mixture is stirred and spends the night with acetate.Vacuum is removed most of volatile matter, NaOH (1N) is added in the crude product, and with twice of ethyl acetate extraction.With ethyl acetate layer drying (Na 2SO 4), filter and concentrate.(0% to 4% methyl alcohol/CH to carry out the flash chromatography post 2Cl 2), obtain required product (27.6mg, 45%).MS(ESI)[M+H +]＝319.35。
Embodiment 15
Figure BPA00001276869200782
(6R, 9R)-6-(2, the 3-difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also for 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid
(6R, 9R)-6-(2, the 3-difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol (27.6mg 0.087mmol) under agitation uses benzene azeotropic.In room temperature with sodium hydride (20.80mg, 0.867mmol) be added to (6R, 9R)-6-(2, the 3-difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol (27.6mg, 0.087mmol) and 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) (43.2mg is in THF 0.113mmol) (3mL) suspension for piperidines-1-carboxylic acid 4-nitrophenyl ester.Reaction mixture is spent the night in this temperature stirring.The cancellation of reaction mixture water also distributes between ethyl acetate and water.The ethyl acetate layer water is washed twice again, dry then (Na 2SO 4), filter and concentrate.(0% to 4% to 8% methyl alcohol/CH to carry out the flash chromatography post 2Cl 2), obtain required product (19.8mg, 36%).MS (ESI) [M+H +]=563.35; 1H NMR (500MHz, and the δ ppm10.30 of chloroform-d) (wide unimodal, 1H) 8.08 (d, J=5.49Hz, 1H) 7.95-8.05 (m, 1H) 7.37-7.53 (m, 1H) 6.94-7.14 (m, 4H) 6.79 (wide unimodal, 1H) 6.00 (d, J=10.38Hz, 1H) 4.66 (wide multiplets, 3H) 3.32 (t, J=12.67Hz, 1H) 3.08 (wide multiplets, 2H) 2.91-3.02 (m, 6H) 2.29 (d, J=13.73Hz, 2H) 2.13-2.24 (m, 2H) 1.86-2.07 (m, 2H) 1.20-1.40 (m, 3H) 0.75-0.98 (m, 1H).
Intermediate 83
(6R, 9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-1-oxide compound also
(1.239g is added to 5.53mmol) that (6R, 9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine (2.17g, CH 5.03mmol) also with mCPBA (metachloroperbenzoic acid) in room temperature 2Cl 2(30mL) in the solution.With reaction mixture in stirred overnight at room temperature.Solvent removed in vacuo.Product comes purifying (with 0% to 50% to 85% ethyl acetate/hexane wash-out) by the flash chromatography post.Chromatographic column obtains product (1.572g, 69%) thus with 85% ethyl acetate/hexane wash-out.MS (ESI) [M+H +]=448.21; 1H NMR (400MHz, and the δ ppm8.14 of chloroform-d) (wide unimodal, 1H) 6.94-7.11 (m, 2H) 6.84-6.92 (m, 2H) 6.66-6.72 (m, 1H) 6.42 (t, J=4.28Hz, 1H) 4.04 (dd, J=14.73,4.41Hz, 1H) 3.73-3.88 (m, 1H) 2.96 (dd, J=14.48,5.41Hz, 1H) 2.50 (d, J=5.79Hz, 1H) 2.13-2.25 (m, 2H) 1.80-1.94 (m, 1H) 1.18-1.32 (m, 3H) 1.09 (d, J=7.55Hz, and 9H) 1.00 (d, J=7.55Hz, 9H).
Intermediate 84
Figure BPA00001276869200792
(6R, 9R)-6-(2, the 3-difluorophenyl)-9-hydroxyl-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-1-oxide compound also
Room temperature with TBAF (4.18mL, 4.18mmol) be added to (6R, 9R)-6-(2, the 3-difluorophenyl)-9-(triisopropyl silyl oxygen base)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-1-oxide compound (1.56g is in THF 3.48mmol) (10mL) solution.Reaction mixture is finished in stirring at room 2 hours and LCMS demonstration reaction.Solvent removed in vacuo, crude product is loaded on the flash chromatography post and with 0% to 10% methyl alcohol/CH 2Cl 2Wash-out obtains required product (0.7662g, 75%), and it is a yellow solid.MS (ESI) [M+H +]=292.10; 1H NMR (400MHz, δ ppm 8.16-8.26 (m, 1H) 7.14-7.20 (m of chloroform-d), 1H) 6.98-7.12 (m, 3H) 6.90 (td, J=7.55,1.76Hz, 1H) 5.38-5.48 (m, 1H) 3.24-3.47 (m, 2H) 3.02 (dd, J=14.60,1.76Hz, 1H) 2.27-2.44 (m, 3H) 1.79-1.94 (m, 1H).
Intermediate 85
Figure BPA00001276869200801
(R)-and 6-(2, the 3-difluorophenyl)-9-oxo-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-1-oxide compound also
(1.227g is added to 2.89mmol) that (6R, 9R)-6-(2, the 3-difluorophenyl)-9-hydroxyl-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-1-oxide compound (0.7662g, CH 2.63mmol) also with the high idodine of Dai Si-Martin in room temperature 2Cl 2(8mL) in the solution.With reaction mixture stirring at room 1 hour.Reaction mixture directly is loaded on the chromatographic column also with 10% methyl alcohol/CH 2Cl 2Separate (gradient is 0% to 10%) (0.54g, 42%).MS(ESI)[M+H +]＝290.03。
Intermediate 86
Figure BPA00001276869200802
(R)-and 2-(tertiary butyl amino)-6-(2, the 3-difluorophenyl)-7,8-dihydro-5H-ring heptan is [b] pyridine-9 (6H)-ketone also
At 0 ℃ with 4-toluene sulfonic acide acid anhydride (0.930g, 2.85mmol) be added to (R)-6-(2, the 3-difluorophenyl)-9-oxo-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-1-oxide compound (0.412g, 1.424mmol) and 2-methyl-prop-2-amine (0.604mL, phenylfluoroform 5.70mmol) (3mL)/CH 2Cl 2(3.00mL) in the suspension.Reaction mixture was stirred 30 minutes at 0 ℃, dilute with ethyl acetate then.Crude product NaOH (1N) washed twice, separating ethyl acetate layer, dry (Na 2SO 4), filter and concentrate.Carry out flash chromatography post (0% to 40% to 60% ethyl acetate/hexane), obtain required product (0.1861g, 38%).MS (ESI) [M+H +]=345.1; 1H NMR (400MHz, δ ppm 7.18 (d, the J=8.56Hz of chloroform-d), 1H) 6.95-7.10 (m, 2H) 6.82-6.95 (m, 1H) 6.60 (d, J=8.56Hz, and 1H) 4.95 (wide unimodal, 1H) 3.45-3.58 (m, 1H) 2.91-3.05 (m, 3H) 2.73-2.85 (m, 1H) 2.13-2.27 (m, 1H) 1.95-2.11 (m, 1H) 1.43 (s, 9H).
Intermediate 87
Figure BPA00001276869200811
(6R, 9R)-2-(tertiary butyl amino)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
Room temperature with sodium borohydride (0.072g 1.893mmol) is added to (R)-2-(tertiary butyl amino)-6-(2, the 3-difluorophenyl)-7,8-dihydro-5H-ring heptan also [b] pyridine-9 (6H)-ketone (0.2173g is in MeOH 0.631mmol) (10mL) solution.With reaction mixture stirring at room 1 hour.LCMS demonstration reaction is finished.Solvent removed in vacuo.Crude product separates (with 0% to 35% to 65% ethyl acetate/hexane wash-out) by the flash chromatography post, obtains two compounds.Title compound is the less compound of polarity (134.9mg, 61%).HPLC t R=2.43 minutes; MS (ESI) [M+H +]=347.33; 1HNMR (400MHz, δ ppm 7.18 (d, J=8.06Hz, 1H) 6.99-7.11 (m, 3H) 6.28 (d of chloroform-d), J=8.06Hz, 1H) 4.76 (dd, J=11.33,2.01Hz, 1H) 4.53 (wide unimodal, 1H) 3.03 (d, J=13.85Hz, 1H) 2.89 (d, J=4.28Hz, 1H) 2.64 (d, J=14.10Hz, 1H) 2.28 (dd, J=12.59,2.01Hz, 1H) 2.13 (dd, J=9.82,3.78Hz, 2H) 1.58-1.71 (m, 1H) 1.42-1.55 (m, 9H).
Intermediate 88
(6R, 9S)-2-(tertiary butyl amino)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol also
The polarity bigger compound (51.1mg, 23%) of title compound for obtaining by above-mentioned reaction.HPLC t R=2.31 minutes; MS (ESI) [M+H +]=347.33; 1H NMR (400MHz, δ ppm 6.85-7.10 (m, 3H) 6.72-6.79 (m of chloroform-d), 1H) 6.24 (d, J=8.31Hz, 1H) 4.84 (dd, J=9.69,3.15Hz, 1H) 4.40-4.56 (m, 1H) 3.44-3.56 (m, 1H) 2.92-3.07 (m, 2H) 2.14-2.25 (m, 1H) 2.05-2.13 (m, 2H) 1.84-1.99 (m, 1H) 1.38-1.55 (s, 9H).
Embodiment 16
Figure BPA00001276869200821
(6R, 9R)-2-(tertiary butyl amino)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also for 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid
(6R, 9R)-2-(tertiary butyl amino)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol (69.1mg 0.199mmol) under agitation uses benzene azeotropic.In room temperature with sodium hydride (47.9mg, 1.995mmol) be added to (6R, 9R)-2-(tertiary butyl amino)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-alcohol (69.1mg, 0.199mmol) and 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) (238mg is in THF 0.299mmol) (3mL) suspension for piperidines-1-carboxylic acid 4-nitrophenyl ester and triethylamine (1: 3) tri hydrochloride.With reaction mixture in stirred overnight at room temperature.The cancellation of reaction mixture water also distributes between ethyl acetate and water.Ethyl acetate layer washes twice with water, dry then (Na 2SO 4), filter and concentrate.(0% to 10% methyl alcohol/CH to carry out the flash chromatography post 2Cl 2), obtaining required product, it is a white solid.Product is further purified (69.2mg, 26%) by preparation property HPLC. 1H NMR (500MHz, δ ppm 8.07 (d, the J=5.19Hz of chloroform-d), 1H) 7.34-7.44 (m, 1H) 6.96-7.15 (m, 4H) 6.08-6.28 (m, 1H) 5.83-5.99 (m, 1H) 4.42-4.77 (m, 3H) 3.16-3.25 (m, 1H) 2.86-3.14 (m, 3H) 2.62-2.72 (m, 1H) 2.11-2.38 (m, 5H) 1.94 (d, J=11.90Hz, 3H) 1.52-1.60 (m, 1H) 1.46 (s, 9H).
Embodiment 17
Figure BPA00001276869200831
(6R, 9R)-2-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also for 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid
With 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6R, 9R)-2-(tertiary butyl amino)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan also [b] pyridine-9-base ester (0.1537g, 0.117mmol) and TFA (4mL, mixture heating up to 70 1.18E+04mmol) ℃ and keeping 1 hour.LCMS shows that most of starting raw materials are converted into required product.There is no indication that carbamate is hydrolyzed to alcohol.Vacuum is removed TFA and crude product is distributed between ethyl acetate and NaOH (1N).The separating ethyl acetate layer, dry (Na 2SO 4), filter and concentrate.(0% to 3.5% to 5% methyl alcohol/CH to carry out the flash chromatography post 2Cl 2).Required product does not have wash-out to come out at this moment.The flash chromatography post continues with 5% methyl alcohol/CH 2Cl 2Wash-out obtains required product, and it is white solid (64.8mg, 90%).MS (ESI) [M+H +]=535; 1H NMR (400MHz, and the δ ppm 11.44 of chloroform-d) (wide unimodal, 1H) 8.13 (d, J=4.53Hz, and 1H) 7.36 (wide unimodal, 1H) 7.14-7.24 (m, 1H) 6.99-7.10 (m, 4H) 6.37 (d, J=7.55Hz, 1H) 5.87 (d, J=10.32Hz, 1H) 5.57 (d, J=1.51Hz, 1H) 4.48-4.83 (m, 2H) 4.17 is (wide unimodal, 1H) 3.23 (dd, J=13.72,11.96Hz, 1H) 2.95 (d, J=10.32Hz, 3H) 2.69 (d, J=14.10Hz, 2H) 2.08-2.31 (m, 3H) 1.83-2.08 (m, 3H) 1.19-1.35 (m, 1H) 0.81-0.95 (m, 1H).
Embodiment 18
(6R, 9R)-6-(2, the 3-difluorophenyl)-2-(dimethylamino)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also for 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid
In room temperature with sodium cyanoborohydride (108mg, 1.721mmol) be added to 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6R, 9R)-2-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester (46mg also, 0.086mmol) and formaldehyde (1mL is in acetonitrile 13.43mmol) (2mL) solution.With reaction mixture stirring at room 4 hours.(0.5mL 8.73mmol) is added in the reaction mixture and reaction mixture is stirred and spend the night with acetate.Vacuum is removed most of volatile matter, NaOH (1N) is added in the crude product and stirring at room 1 hour, uses ethyl acetate extraction then.With ethyl acetate layer drying (Na 2SO 4), filter and concentrate.(0% to 4% to 8% methyl alcohol/CH to carry out the flash chromatography post 2Cl 2), obtain required product (19.8mg, 39%).MS(ESI)[M+H +]＝563.42。
Embodiment 19
Figure BPA00001276869200841
(6R, 9R)-2-chloro-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also for 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid
At-5 ℃ to 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6R, 9R)-2-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester (45mg also, 0.084mmol) and hydrochloric acid (3mL, 36.5mmol) mixture in add cuprous chloride (I) (16.67mg, 0.168mmol) and SODIUMNITRATE (21.47mg, 0.253mmol).Reaction mixture was stirred 1 hour and stirring at room 1 hour in this temperature.NaOH (1N) is added in the reaction mixture, uses ethyl acetate extraction then twice.Ethyl acetate layer salt water washing separates then, dry (Na 2SO 4), filter and concentrate.(0% to 4% to 8% methyl alcohol/CH to carry out the flash chromatography post 2Cl 2), obtain required product (6.4mg, 12%).MS(ESI)[M+H +]＝554.09。
Intermediate 89
Figure BPA00001276869200842
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid 4-nitrophenyl ester
With 2-oxo-1-(piperidin-4-yl)-2,3-dihydro-1H-imidazo [4,5-b] pyridine-4-muriate (2-oxo-1-(piperidinium-4-yl)-2,3-dihydro-1H-imidazo[4,5-b] pyridin-4-iumchloride) (10.41g, 35.8mmol) mixture in THF (300mL) and DMF (167mL) stirred 10 minutes under room temperature and nitrogen.Reaction mixture still is suspension at this moment.(27.5mL 250mmol) slowly is added in the reaction mixture with the 4-methylmorpholine.Internal reaction temperature becomes 22 ℃ by 20 ℃.With reaction mixture restir 10 minutes, then at the disposable adding 4-of room temperature (2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid 4-nitrophenyl ester.Temperature of reaction rises to 27 ℃.Reaction mixture was stirred 2 hours.1000mL water slowly is added in the reaction mixture, all suspension dissolvings, solution becomes muddiness then.With reaction mixture in stirred overnight at room temperature.Reaction mixture is filtered and solid water and CH 3The CN washing.Product and 79044-022 are merged, and it is pale powder (7.4g, 54%) and in statu quo uses.
Embodiment 20
Figure BPA00001276869200851
(6R, 9R)-2-chloro-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also for 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid
Under nitrogen, in the 1L round-bottomed flask of oven dry, in DMF (200mL), add (6R, 9R)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-alcohol (12.74g also, 46.3mmol) (purity＞99.9%) and 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid 4-nitrophenyl ester (26.6g, 69.4mmol), obtain faint yellow suspension.After being cooled to-15 ℃ with the MeOH-ice bath, dropwise add NaHMDS (139mL, 139mmol).After forming gel (adding 1.5 equivalent alkali), remove cooling bath and dropwise add remaining alkali.Mixture was stirred 2 hours under room temperature and nitrogen.LCMS shows conversion fully.3h: it uses saturated NaHCO 3Solution (400ml) cancellation.Suspension is distributed between 500ml water and 700ml EtOAc.(2 * 250ml) extract with EtOAc to separate each layer and water layer.LCMS confirms that no product is residual in water layer.The organic layer that the merges saturated NaHCO of 300ml 3, 2 * 300ml water and the water washing of 300ml salt, use Na 2SO 4Dry and concentrated, obtain yellow foam/solid.Crude product is used 4%MeOH/CH by FCC (about 900g silica gel) 2Cl 2Purifying.Resulting product (it is the tawny solid) is by being further purified (21.64g, 90%) with the iPrOH recrystallization, it is that (be used for HPLC-MS analyzes white crystalline powder: 99.2%, and enantiomer excessive (ee) is estimated: 100%ee); Fusing point is 248 ℃.
The monocrystalline X-ray measurement
Cu K α radiation is equipped with
Figure BPA00001276869200861
The BrukerAPEX2Kappa CCD diffractometer of rotating anode producer is used for gathering diffraction data in room temperature.With APEX2 software package/package (APEX2 Data Collection and Processing User Interface:APEX2 User Manual, v1.27; BRUKER AXS, INc., 5465 East Cheryl Parkway, Madison, WI 53711USA) measured intensity data is carried out index and processing.Final unit cell parameters uses whole set of data to determine.
Structure is resolved by direct method, and uses SHELXTL software package (Sheldrick, GM.1997 by complete matrix least square law technology, SHELXTL.Structure Determination Programs.Version 5.10, Bruker AXS, Madison, Wisconsin USA) comes refine.The function that is minimized in refine is a ∑ w(| F o|-| F c|) 2R is defined as ∑ || F o|-| F c||/∑ | F o|, and R w=[∑ w(| F o|-| F c|) 2/ ∑ w| F o| 2] 1/2, wherein w is based on the suitable weighting function of intensity observational error.All stages in refine are checked difference fourier figure (difference Fourier map).All non-hydrogen atoms come refine by anisotropy Hot swapping parameter (anisotropic thermal displacement parameter).In final difference fourier figure, the hydrogen atom relevant with hydrogen bond positioned, and calculate by the idealized method of geometry with standard key length and standard key angle the position of other hydrogen atom.They are specified by isotropic temperature factor (isotropic temperature factor), and are included in the structure factor method of calculation with preset parameter.
The following demonstration of crystal data of embodiment 20 compounds.The hierarchical atoms coordinate is listed in the table 2.It will be understood by those skilled in the art that the subtle change in the coordinate is possible and is considered to be within the purview.Temperature: room temperature; Wavelength: 0.71070; Crystallographic system, spacer: iris, P2 (1) 2 (1) 2 (1); Unit cell dimension: a=7.5941 (1) A, α=90 °; B=13.8789 (2) A, β=90 °; C=24.7319 (3) A, γ=90 °; Volume: 2606.69 (6) A 3Z, bulk density: 4,1.324Mg/m 3
Atom X Y Z U(eq)
O(1) -3138(3) -3128(1) -795(1) 52(1)
O(2) -4445(3) -2737(1) -1587(1) 59(1)
O(3) 874(3) -7046(2) -2345(1) 76(1)
N(1) -249(3) -2383(2) -1185(1) 59(1)
N(2) -3324(3) -4230(2) -1451(1) 58(1)
N(3) 752(3) -5384(2) -2444(1) 59(1)
N(4) 2908(4) -6179(2) -2849(1) 60(1)
N(5) 4345(4) -4861(2) -3287(1) 67(1)
F(1) -5198(4) 864(2) -133(1) 120(1)
F(2) -6096(7) 2376(2) 450(2) 169(2)
C(1) -4103(7) 1133(3) 266(1) 86(1)
C(2) -4607(9) 1936(3) 572(2) 110(2)
C(3) -3566(11) 2247(3) 987(2) 117(2)
Atom X Y Z U(eq)
C(4) -2071(10) 1750(4) 1105(2) 115(2)
C(5) -1557(6) 961(3) 798(2) 88(1)
C(6) -2606(5) 631(2) 368(1) 69(1)
C(7) -2092(4) -273(2) 61(1) 60(1)
C(8) -1890(5) -73(2) -550(1) 66(1)
C(9) -732(4) -785(2) -837(1) 59(1)
C(10) 892(5) -517(3) -1040(1) 75(1)
C(11) 1939(5) -1169(3) -1310(1) 76(1)
C(12) 1308(4) -2088(3) -1376(1) 66(1)
C(13) -1215(4) -1750(2) -914(1) 51(1)
C(14) -2915(4) -2126(2) -662(1) 50(1)
C(15) -2877(4) -2071(2) -46(1) 54(1)
C(16) -3363(4) -1096(2) 186(1) 60(1)
C(17) -3664(3) -3316(2) -1307(1) 49(1)
C(18) -3817(4) -4559(2) -1991(1) 66(1)
C(19) -2208(4) -4617(2) -2360(1) 67(1)
C(20) -805(4) -5238(2) -2104(1) 60(1)
C(21) -320(4) -4856(2) -1544(1) 60(1)
C(22) -1952(5) -4816(2) -1191(1) 65(1)
C(23) 1452(4) -6298(2) -2527(1) 59(1)
C(24) 3110(4) -5225(2) -2978(1) 54(1)
C(25) 4272(5) -3902(3) -3342(2) 79(1)
C(26) 3046(6) -3334(3) -3100(2) 85(1)
C(27) 1738(5) -3728(2) -2770(2) 73(1)
C(28) 1776(4) -4716(2) -2715(1) 56(1)
Embodiment 21
(1-(((6R, 9R)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base oxygen base also) carbonyl) piperidin-4-yl)-2-oxo-1, the 2-glyoxalidine is [4,5-b] pyridine-3-negatively charged ion sylvite also for 1-
In the 100mL round-bottomed flask of oven dry, in ethanol (10mL), add 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6R, 9R)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-encircles heptan, and also [b] pyridine-(1.08g 2.079mmol), obtains colourless solution to 9-base ester.Disposable adding potassium tert.-butoxide (0.233g, 2.079mmol).Heating gun is used for mild heat solution and rotates up to solid simultaneously and dissolve fully.Remove volatile matter, obtain white foam shape thing/powder.With powder further dry and warm frequently (50 ℃ of baths) under high vacuum, under room temperature and high vacuum dry 3 days then.Obtain LCMS and HPLC.HPLC shows that purity is 98% and does not have single impurity purity＞0.5%. 1H NMR (400MHz, and d6-DMSO) 8.44 (s, 1H), 7.61-7.55 (m, 2H), and 7.31-7.21 (m, 4H), 6.91 (s, 1H), 6.41 (s, 1H), 5.93 (d, J=12Hz, 1H), 4.38 (broad peak, 2H), 4.11 (broad peak, 1H), 3.50-3.41 (m, 1H), 3.21-2.78 (m, 5H), 2.30-1.50 (m, 7H).
It will be understood by those skilled in the art that the disclosure is not limited to above-mentioned illustrative examples, and it can be implemented with other specific form under the situation that does not depart from its essential attribute.Therefore, in any case embodiment should be schematic and nonrestrictive, should be with reference to appended claims but not the foregoing description, therefore all changes of carrying out in the implication of equal value of claims and scope all will contain in this application.

Claims (23)

1. the compound or pharmaceutically acceptable salt thereof of formula I:
Figure FPA00001276869100011
Wherein
R 1Be hydrogen, cyano group, halogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, alkyl SO 2, amino, alkylamino, dialkyl amido, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, N-alkylpiperazine base or morpholinyl;
R 2Be selected from a following substituent piperidyl for being substituted with:
Figure FPA00001276869100012
Or R 2For
Figure FPA00001276869100013
R 3Be hydrogen, halogen, cyano group, alkyl, haloalkyl, alkoxyl group or halogenated alkoxy;
R 4Be hydrogen, halogen, cyano group, alkyl, haloalkyl, alkoxyl group or halogenated alkoxy;
Ar 1Be selected from following 0-3 substituent phenyl for being substituted with: cyano group, halogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy and alkyl SO 2
X is O, CH 2Or NH; And
Y is chemical bond, O, CH 2Or NH.
2. the compound of claim 1, it has following stereochemistry:
Figure FPA00001276869100021
3. the compound or pharmaceutically acceptable salt thereof of claim 2, wherein
R 1Be hydrogen, halogen, cyano group, amino, alkylamino or dialkyl amido;
R 2Be selected from a following substituent piperidyl for being substituted with:
Figure FPA00001276869100022
R 3Be hydrogen or halogen;
R 4Be hydrogen or halogen;
Ar 1For being substituted with the phenyl of 0-2 halogenic substituent;
X is O, CH 2Or NH; And
Y is O.
4. the compound or pharmaceutically acceptable salt thereof of claim 3, wherein R 1Be hydrogen, chlorine, cyano group, amino, dimethylamino or tertiary butyl amino; R 2Be selected from a following substituent piperidyl for being substituted with:
Ar 1Be phenyl or difluorophenyl; X is O, CH 2Or NH; And Y is O.
5. the compound of claim 1, wherein R 1Be hydrogen, halogen or cyano group.
6. the compound of claim 1, wherein R 2Replace for the N-piperidyl and at 4.
7. the compound of claim 6, wherein said substituting group is
Figure FPA00001276869100024
8. the compound of claim 1, wherein Ar 1For being substituted with the phenyl of 2 halogenic substituents.
9. the compound of claim 1, wherein Ar 1Be 2, the 3-difluorophenyl.
10. the compound of claim 1, wherein X is O.
11. the compound or pharmaceutically acceptable salt thereof of claim 1, described compound is selected from:
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid 5-(2, the 3-difluorophenyl)-2-oxo suberyl ester;
4-(2-oxo-4,5-dihydro-1H-benzo [d] [1,3] diaza
Figure FPA00001276869100031
-3 (2H)-yl) piperidines-1-carboxylic acid (6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also; With
2-oxo-1, [benzo [d] [1,3] oxazine-4,4 '-piperidines]-1 '-carboxylic acid (6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also for 2-dihydro spiral shell.
12. the compound or pharmaceutically acceptable salt thereof of claim 1, described compound is selected from:
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6,9-is trans)-2-cyano group-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also;
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6R, 9R)-2-chloro-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also;
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6S, 9S)-2-chloro-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also;
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6,9-is trans)-6-phenyl-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also;
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6,9-is trans)-6-(2, the 5-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also; With
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6,9-is trans)-6-(3, the 4-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also.
13. the compound or pharmaceutically acceptable salt thereof of claim 1, described compound is selected from:
1-(1-(2-((6, the 9-cis)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) ethanoyl) piperidin-4-yl)-1H-imidazo [4,5-b] pyridines-2 (3H)-ketone;
1-(1-(2-((6R, 9S)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) ethanoyl) piperidin-4-yl)-1H-imidazo [4,5-b] pyridines-2 (3H)-ketone;
1-(1-(2-((6S, 9R)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also) ethanoyl) piperidin-4-yl)-1H-imidazo [4,5-b] pyridines-2 (3H)-ketone;
N-((6R, 9R)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also)-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide; With
N-((6S, 9S)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also)-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide.
14. the compound or pharmaceutically acceptable salt thereof of claim 1, described compound is selected from:
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6R, 9R)-2-(tertiary butyl amino)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also;
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6R, 9R)-2-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also;
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6R, 9R)-6-(2, the 3-difluorophenyl)-2-(dimethylamino)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also;
N-((6R, 9R)-3-amino-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-yl also)-4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-methane amide; With
(6R, 9R)-6-(2, the 3-difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also for 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid.
15. the compound or pharmaceutically acceptable salt thereof of claim 1, described compound is selected from:
4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b] pyridine-1-yl) piperidines-1-carboxylic acid (6,9-is trans)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base ester also; With
(1-(((6R, 9R)-6-(2, the 3-difluorophenyl)-6,7,8,9-tetrahydrochysene-5H-ring heptan is [b] pyridine-9-base oxygen base also) carbonyl) piperidin-4-yl)-2-oxo-1, the 2-glyoxalidine is [4,5-b] pyridine-3-negatively charged ion sylvite also for 1-.
16. compound or pharmaceutically acceptable salt thereof, described compound is:
Figure FPA00001276869100041
17. the compound of claim 16, wherein said pharmaceutical salts are sylvite.
18. a composition, it comprises the compound or pharmaceutically acceptable salt thereof and the pharmaceutical carrier of claim 1.
19. the composition of claim 18, the compound of wherein said claim 1 are following compound or pharmaceutically acceptable salt thereof:
Figure FPA00001276869100051
20. the method for the illness that treatment is relevant with unusual CGRP level, it comprises the compound or pharmaceutically acceptable salt thereof to the claim 1 of patient's drug treatment significant quantity.
21. the method for claim 20, wherein said illness are migraine.
22. the method for claim 20, the compound of wherein said claim 1 are following compound or pharmaceutically acceptable salt thereof:
Figure FPA00001276869100052
23. the method for claim 22, wherein illness is a migraine.
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